This paper presents the modelling of wear data resulting from linear dry contact using artificial neural networks (ANN) and adaptive neuro-fuzzy inference systems (ANFIS) with the aim of constructing predictor models for the depth and volume of the wear scar, with great impact in the characterization of new industrial processes utilizing existing materials. The dataset is the result of laboratory testing, presenting both numerical and categorical variables whose inclusion into the model allows for a number of possibilities. The width of the wear scar was measured on a microscope, and its depth was calculated. A multitude of experimental tests was performed with normal loads and different speeds, which led to some conclusive results, but in some cases, with relatively high variance. Various options for the automatic generation of fuzzy inference systems were also approached (genfis2). The innovative approach was compared with a baseline model featuring multivariate linear regression optimized using gradient descent, drawing on previous experimentation on the same dataset. The models developed can be implemented in future research and in practical applications under similar conditions, aiming to optimize performance by applying Computer Science. The obtained results lead to highly accurate prediction models which are further integrated into various metallic surface characterizations in the wear process for tribological and robotics research in new industrial processes using short glass fiber reinforced polymers. The paper presents new intelligent analytical methods for the characterization of wear in thermoplastic materials armed with short glass fibers (SGF) and steel in a dry contact wear scenario, applied to new industrial processes using existing materials.Wear phenomena are very complex within injection or extrusion machine cylinders. The tribological hostile environment, high temperature, and corrosive chemical compounds increase this complexity. In the case of processing thermoplastic materials with short glass fiber fillings, complexity is further increased because of their significant abrasion.The mechanical interaction in the form of wear, which always appears between two or multiple bodies when there are relative speeds, sliding, rolling, pivoting, and so on, defines friction wear. The process complexity is determined by the wear indicators, among which are the linear wear intensity, volumetric wear intensity, gravimetric wear intensity, wear coefficient, wear sensibility coefficient, and apparent energy density.Previous studies on friction couples with linear contact on thermoplastic material armed with short glass fibers (SGF) and steel in a dry friction context have shown in experiments that even under normal, relatively small loads, large contact pressures and therefore very high contact temperatures may appear, which are close or may even exceed the transformation temperature of the plastic material.These lead to the need to approach modelling as a dependency between the various variables of interest involved in the friction process and metallic surface characterization in the wear process using advanced statistical and optimization algorithms on a dataset obtained from hardware simulation. The subject draws from growing interest from the research community with the advent of highly advanced, intelligent classification; optimization and regression algorithms; and the wide impact of metallic surface characterization applications in the wear process, emphasizing the abrasive, adhesive, and corrosive wear.Zhang et al.  analyzedSimilar directions were investigated in Panda et al. and Flepp ,3 regardWear processes, similar to fabrication processes, involve very complex and nonlinear phenomena. Consequently, analytical models are difficult or impossible to come by. However, improvements in the performance and reliability of mechanical equipment and production instruments require precise modelling and prediction of the wear phenomenon. Artificial neural networks (ANNs) and the related methods investigated in this paper, such as neuro-fuzzy inference systems, possess many desirable properties for modelling systems and processes: the ability to approximate universal functions, learning from experimental data, high tolerance for lacking or noisy data, and good capacity for generalization.Artificial neural networks are the driving force behind the current advances in artificial intelligence, with useful applications in virtually every computational field. They rely on successively improving a network of weights attached to hidden units called neurons. Neural networks work by solving for the best dynamic weights of a hidden layer of neurons, which determine the strength with which these are fired . While sShukla  reportedThe same nonlinearity was found by Căpitanu et al.  in the bThe baseline model considered for expressing a dependency between the various variables of interest involved in the friction process and metallic surface characterization in the wear process is a multivariate linear regression. The first step in a multiple variable regression model is to normalize the features and then run a batch gradient descent algorithm on the data, where each iteration minimizes the cost function by simultaneously updating all variable coefficients . The linThe resulting dataset is then used to train a linear regression model for each of the two considered dependent variables: Wear depth and wear volume. This model assumes the dependent variables to be a linear combination of the considered independent variables, speed and pressure, and an intercept term, which does not vary with the independent variables. The intercept term is added only for the linear regression problem since the neural network algorithm will do the same on its own.The optimization problem is then to find the best coefficients that minimize the cost function, which gives a measurement of the difference between the empirical values of the two dependent variables and their estimates obtained through linear regression. Gradient descent is the algorithm used to iteratively arrive at the best possible set of variable coefficients. The learning rate for this version of gradient descent is set to 1.For each dependent variable, the prediction is a dot-product of the independent variable values and its respective coefficient vector. The linear regression coefficients show the relative influence a certain independent variable has on the prediction of a dependent variable. The intercept term is a baseline starting point for the prediction models, being an aggregation of all the other factors not considered and the inherent randomness of the model.Fuzzy logic and fuzzy inference systems extend regular logic systems by assigning a degree of membership to elements within sets, which proves to be a very useful ability for modelling complex, unknown, or dynamic systems. Fuzzy Logic has long been used in academia and in industry and is one of the more palpable staples of artificial intelligence in the world today. Fuzzy logic controllers have proven to be robust and relatively easy to design . They seANFIS implementations in the context of wear prediction deals mainly with fault prevention and monitoring. Zuperl and Cus  construcThe provenance of the initial fuzzy inference system is of great significance in designing an ANFIS algorithm. Fuzzy inference systems may be automatically obtained from the available data through a number of algorithms, which mainly attempt to group the available data-points into equivalent fuzzy sets and then deduce relations between them, which turn into a set of fuzzy rules. The resulting fuzzy inference systems (FIS) can be used to seed an ANFIS algorithm, that is, to have it start optimization from the previously obtained FIS. In fact, if no seed is specified, the ANFIS algorithm will itself use one of the methods, namely grid partitioning, to generate its starting FIS. As is traditional with ANFIS, all of the FISs investigated were of the Sugeno type due to complexity and computational constraints. In addition, because of the limited amount of data, the generated fuzzy inference systems themselves are considered as possible solutions for the proposed model, since ANFIS models are very susceptible to over-fitting the data in the present context.The authors have had previous contributions to this and related topics in ,12,15,16The remainder of this paper is divided as follows. The study of injection and extruding processes for thermoplastic materials is a complex process due to the phenomena existing inside injection and extruding machines with a permanent interconnection of the influencing factors.2 (titanium dioxide) or graphite fibers, the technological process implies transforming the material from a solid to a plastic/liquid phase, which is achieved at temperatures above 1600 °C, with the material suffering deformation, pressing, and heating depending on the machine and the technological process.Starting from the material selection stage, either fine dust, or the quantity of short glass fibers (SGF) used, adding materials such as TiOIn addition to the material complexity and the preparation for injection, an important part is played by determining a predictive model for the wear process in order to increase wear resistance of the work surfaces of the injection and extruding machines.These are some of the considerations for the neuro-fuzzy modelling of wear data resulting from linear dry contact using artificial neural networks (ANN) and adaptive neuro-fuzzy inference systems (ANFIS).Wear performance of the two steel alloys, C120 and Rp3, has been previously studied in the case of linear dry contact with each polymer (polyamide and polycarbonate) reinforced with different percentages of short glass fibers (SGF). The functional diagram of the friction couple is presented in The wear scar occurs by penetration of the cylindrical liner, under the influence of the normal load, in the flat sample material. In theory, the holding thimble is considered as rigid and relatively small in view of the backside imprint, so it can be considered as made up of a sum of cylinder areas. This is illustrated schematically in Căpitanu et al. .E2A = 40.25 MPa.Nylonplast AVE Polyamide + 30% glass fibres; E2B = 31.76 MPa.Noryl Polyamide + 20% glass fibres; E2C = 42.08 MPa.Lexan Polycarbonate + 20% glass fibres; We considered the following three polymers:E) listed above, and the deformed liner radii (r2), imposing pmax is provided as H is the Brinell hardness for the plastic liner, enough so that it will not be crushed. The approximate depth of the wear scar is calculated with the relation: h ≈ l2/8r2.Numerical values were determined by the elasticity modules  reinforced with SGF, the five normal loads (contact pressures), indexes 1 to 5 of notations of the pressures that have been subjected to tests, for each of the seven relative sliding speeds used :After inspecting and measuring the wear scars of the metal surfaces, the widths of each wear scar were measured and their volume was calculated . Their variation curves were also traced depending on the applied load (contact pressure), the relative speed of sliding contact with the temperature specification of the optical image and the presentation of the scar. This quantitative–qualitative assessment was presented in Căpitanu et al. . All tesThe increased friction coefficient entails increasing the wear rate and contact temperature, but after our data, it has not yet been possible to establish a mathematical relationship between the two sizes, which is widely recognized. This is why a suggestive graphical representation was sought to provide a qualitative correlation between the two sizes that relates them to the contact temperature and based on which to determine a quantitative correlation.Ra), shows a strong nonlinearity due to the behavior of the elastic-plastic polymers tested. In this situation, we tried an approach to model metal surface wear through advanced data fitting algorithms, because of their ability to model very complex and strongly nonlinear phenomena. This was the qualitative–quantitative analytical approach previously achieved. The graphic processing of these results was presented in Căpitanu et al. [All the variation curves of the output parameter of the frictional system  depending on input parameters, normal load (contact pressure), the sliding speed while maintaining the steady state surface  and outputs  influence each other continually.The resulting dataset includes the following information, seen in Mode is whether the variable is treated as a dependent or an independent variable. The contention of any modelling technique is that the dependent variables can be represented as some relation, whether explicit or implicit, of the independent variables. In the present context, the paper investigates the effect of various materials, speeds, and pressures on the depth and volume of the wear scar.Range shows the numerical limits of each considered variable.Unit displays the unit of measurement for each variable.Type is one of three possibilities for the nature of the variable: Numerical, categorical, or ordinal . The latFor each of the variables considered, the table describes the following characteristics:For the material type, there are three possible options since a fitting application cannot work with simple labels as inputs. The first is not considered proper, and is only shown as a comparison to the other two. The second and third options lead to separate optimization problems, both of which are considered in parallel for each of the models involved. The first is coding the categorical variable as a simple numerical variable, with different integer numbers for each of the labels. For example, each of the material combinations used in the experiments can be assigned an integer, transforming it into a discrete numerical variable and allowing it to interact with the rest of the independent numerical variables.However, this suffers from implicitly ordering the labels, which would negatively impact the model and possibly introduce hidden biases, since the assigned numbers have no mathematical meaning .The second option is coding the categorical variable into multiple binary variables, one for each of the material labels. This is especially advantageous in the present context, since each value of the categorical variable is logically a combination of two materials, the scratched surface and the object used for scratching. As an aside, this was also possible for the first representation, but it further increased the danger of misrepresentation through the interaction of numerical labels. The second representation is shown in Each of the materials that make up the labels of the categorical variable will be binary variables themselves. The binary representation translates naturally to whether that particular material is present or not. This is the standard representation and is implemented in some of the models. The main drawback is that the scarcity of the resulting matrices may lead to rank deficiency in some of the methods for automatically generating fuzzy inference systems (genfis). max, Pmax and Nimax—are introduced. The chosen variables have a full complement of values for each of the materials used in the experiment. The eight new variables are shown in The third option is replacing the categorical variable altogether. Instead of using the material labels, the model will introduce, as independent variables, the numerical characteristics of the various materials. To this end, five new variables for the polymers—specific weight, water absorption, elasticity, thermal conductivity and linear dilation—and three for the steel—SThis gives the dataset eight independent variables that describe the variation in material on both sides of the experiment. The higher dimensionality is a slight disadvantage, but the representation is more natural due to them being actual numerical variables. An excerpt of the dataset is shown in In conclusion, the first coding option—simple numerical coding—is not suited to the task, while the second and third options are both used. This will create two distinct learning problems, which will be called the binary coding problem (option 2) and the numerical coding problem (option 3), on which the various algorithms are run. The results are shown and discussed for both cases in the appropriate sections.An example of plotted data is shown in The available data-points were randomly divided into a training set and a test set, with ratios of 70% of the total and 30% of the total, respectively. This is done by constructing a random index of 70% true values on a vector with the same length as the number of lines  in the dataset. The training and test sets are then easily separated based on this index. The training test is used for optimizing the parameters of the various models including hyper-parameters . The test set is not available to any algorithm until the model is complete, when it is used to evaluate its performance on a heretofore unseen set of data belonging to the same phenomenon. Therefore, the evaluation of each model will take place both on the training set as well as on the test set.For metallic surface characterization on linear dry contact between the plastic material reinforced with SGF and alloyed steel, a multitude of experimental tests was performed with normal loads and different speeds, which led to the modelling of the metallic surface characterization on linear dry contact between the plastic material reinforced with SGF and alloyed steel using four predictor models presented below.X is the input data, namely the dependent variables, containing all data-points, plus an intercept term. Y is the output data, alternatively the wear speed or wear volume, that the algorithm is trying to learn, and θ is the matrix of coefficients used to estimate Y from X. The challenge is finding the best coefficients, which minimizes the error between the actual Y and the estimate. This is obtained from The first model is a first-order multivariate linear regression optimized using batch gradient descent. The results obtained here will be used as a baseline for all other models. The optimization problem is described as m features and an intercept term, which helps prevent over-fitting. The total sum of all errors, across all values, is defined as the cost function. It is this cost function that the optimization algorithms attempt to minimize.There will be Gradient descent is an optimization algorithm where the potential solution is improved each iteration by moving along the feature gradient in the variable space. While it requires that the target function be differentiable and it is somewhat susceptible to local minima, gradient descent provides a stable and computationally inexpensive algorithm for function optimization.As noted in the previous chapter, both representations of the dataset, using the two options for coding the categorical variable, were investigated in parallel. After running the gradient descent algorithm, the following coefficients were obtained, as shown in The obtained models will now predict the depth and volume of the wear scar as the linear combination of the vector of thetas and the value of a given feature set.For example, using binary coding, the wear depth will be predicted asThe blue points represent the actual experimental data available for training, while the red points are the estimates that the model would obtain for the same input data.The linear regression model has a decent performance of fitting the training data, but is obviously at a disadvantage because of the non-linearity present in the dataset. One interesting point of note is that the relative influence of the various features can be directly ascertained from the theta values, which shows both the magnitude and the direction of the dependency.Neural network models are centered on a layer of hidden features  which control the prediction. Neural networks have an input layer that matches the considered independent variables and an output layer which matches the dependent variable. The model is optimized by successively tuning the weights associated to these neurons as well as their activation functions. A standard neural network is exemplified in The most important hyper-parameter of a neural network model is the number of neurons in the hidden layer. For the purposes of this application, all models contain 25 hidden neurons. This number was selected after running the algorithm with various levels of neurons and settling on the best performance in terms of the correlation coefficient for both the training and test sets. The training time varies greatly with the choice of training algorithm selected: Some may require only 1–2 s, while some configurations can take up to 30 s. The neural network selected here was timed at 12 s.The weights of the selected neural networks are far too numerous to display in the paper. For example, to pass from the input layer of 10 neurons  to the hidden layer of 25 neurons, a matrix of 25 lines and 10 columns is required. As with the linear regression figures, the blue points are the empirical data and the red points the estimates. It should be noted that perfectly correct estimates (red points) will overwrite the empirical data representation (blue points) where they coincide.Neural networks give a very good fit of the training data. For example, notice how virtually all empirical points in the lower half of the volume fit, as seen in the graphical representation, have been overwritten by their estimates. Such good behavior on the training set, however, always raises suspicions of over-fitting, which will be verified or invalidated when the model is used on the training set.Fuzzy inference systems can be automatically generated and then used as actual models for predicting the future behavior of a system. The generated FIS can then be deployed either as such, or further optimized using an ANFIS algorithm, which will be discussed in the next section. As these tend to be computationally intensive models, the FIS is of the Sugeno type, which employs linear or constant functions as outputs, as opposed to the Mamdani type FIS, whose outputs are also fuzzy membership functions. This type of FIS has fewer parameters and is therefore somewhat less computationally intensive. As will be discussed in the final results section, there is also the danger of over-fitting since there are so many parameters and comparatively few data-points.Given a set of raw data, there are three options for obtaining a working FIS: Grid partitioning (genfis1), subtractive clustering (genfis2), and fuzzy c-means clustering (genfis3). There are a number of hyper-parameters to be tuned such as the number of membership functions per input and the shape of each membership functions. These were chosen after some trials to be four membership functions per numerical variable and two per binary variable, when dealing with the binary coding option. The shape of the membership functions was kept as standard bell curves (Gaussian distributions). Generating fuzzy inference systems is performed quickly, usually within a second. The last run yielding internal timings of 0.177 s for genfis1, 0.153 s for genfis2, and 0.248 s for genfis3.Grid partitioning is really only used as a benchmark, since it is commonly held that its performance is unsatisfactory unless further developed with ANFIS ,24,25. HAs can be seen from From the spread of the empirical and estimated data, some early conclusions can be drawn about generated fuzzy inference systems. As already discussed, grid partitioning is simply an empty form for a FIS, which is the starting point of an ANFIS algorithm, as no attempt is made to fit the experimental data. The FIS obtained through subtractive clustering has near perfect performance on the training set, which naturally raises concerns about the possibility of over-fitting the data. These will be addressed when performing on the test set. The third method, fuzzy c-means clustering, obtains good, if not great, performance and is a very good start for further optimization.ANFIS uses back propagation to determine the premise parameters of each rule. The consequent parameters are then determined using a least mean squares algorithm. An iteration of the learning algorithm consists of two passes: In the forward pass, the premise parameters are fixed and the consequent parameters are optimized through an iterative least squares approach, while going through the rule base system. In the backward pass, the consequent parameters are fixed, while the premise parameters are modified using back propagation. This algorithm continues until the target error is met or the number of iterations exceeds a predetermined threshold. An excellent description of the ANFIS architecture and learning procedure is given by Denai et al. .Adaptive neuro-fuzzy inference systems construct a FIS capable of predicting the values of the dependent variables through further optimization of a generated FIS structure. If no initial FIS is specified, one is created through a genfis1 (grid partitioning) algorithm. With the exception of grid partitioning in the case of numerical coding, as discussed previously, all generated FISs were run through an ANFIS algorithm in the hopes of improving performance. The algorithm is relatively fast, usually lasting a few seconds. It will take longer when starting from a FIS obtained through grid partitioning (genfis1), since it requires more optimization. The inference systems discussed in the paper were timed at 4.987 s for ANFIS 1, 1.019 s for ANFIS 2, and 1.866 s for ANFIS 3.The algorithm was used with a standard set of hyper-parameters such as 50 generations and the inherited FISs obtained at the previous step. The fuzzy inference spaces obtained after running the algorithm have a very interesting configuration. The resulting rule base spaces are clearly nonlinear, which should lead to a good ability to fit the present dataset. The performance shown by all ANFISs is very encouraging as the spreads shown above seem to reveal very good behavior from all systems. Pending the requisite investigation on the test sets, the ANFISs appear to be the frontrunners for fitting the experimental dataset. Of particular note is the near perfect performance obtained in fitting the wear volume.While the figures provide a good overview of the models’ behavior, they fail to give an analytical measure of model performance. For this, two metrics were used, both of which gave a numerical measure of the error: The mean square error (MSE) and the mean absolute error (MAE). Since these are metrics for the error of the model, lower values correlate to better performance. The mathematical expressions are shown below:These two error functions should provide the definitive information on which model best fits the available experimental data. The results are put together into It should first be noted that there is a random element to the above results. No two algorithm runs result in exactly the same models, hence there is some variation in the implementation of the simulation. However, the algorithms have been run multiple times and each set of results supports the general conclusions which are to be drawn from the above tables.The obtained prediction function provides a good fit of the model, with little error and no over-fitting, as can be concluded from the testing phase of the algorithm. Once trained, the predictive model can be used instead of the actual analytical approach in any application where the dependent variables are needed and the independent variable values are available, within a similar context. This reduces the mathematical complexity of the overall application and could find use in a range of computationally intensive models. It is these functions that will be further improved through the addition of more data as it becomes available, and will be used to predict the future behavior of the experiment.The discussion of results revolves around the test scores for the two types of error functions obtained by each model.In judging the various algorithms, a lower value for MSE and MAE norms are preferable since these represent errors in fitting. For example, in modelling the wear volume with binary coding, the ANFIS2 model is preferable to the linear regression as it achieves lower error grades in both MSE and MSE for the training suite (0.004 < 0.067 and 0.033 < 0.159) as well as the test suite (0.02 < 0.095 and 0.11 < 0.17). Furthermore, it is relatively easy to spot an over-fitting model as it will have good to great performance on the training suite, but poor performance on the test suite. This means it fits the available training data too closely and is ill-equipped to handle new incoming data from the same experiment. As an example, Genfis2 fits the training data for wear volume in binary coding perfectly—the errors are actually zero, but it has very large errors when used on the test data (MSE = 1453 and MAE = 10.48).As relates to the coding option being used, the variation in results from binary to numerical coding has generally been minimal. While the numbers are obviously different, the same tendencies exist in both representations of the problem.Linear regression actually performs very well on the test set and in fact overall, suggesting there may be some linear dependencies between the dependent and independent variables after all. It does not provide the level of performance of the neural network or ANFIS models, but as a baseline model, it does very well.The neural network models have the best overall performance in terms of being the most balanced. While occasionally overtaken by some of the ANFIS or even Genfis algorithms, the neural network models always give very good performance, significantly overtaking the baseline models .The Genfis models achieved mixed results. While sometimes showing superb performance, overtaking even the neural networks or some ANFIS models, they are susceptible to dangerous levels of over-fitting. When that happens, the model is virtually useless as it achieves disproportionate error levels on the test sets—see Genfis2 for wear volume fitting in binary coding. Genfis1 was never meant to be an actual fitting model and of course performs the most poorly, although it does have a few instances when it is workable. However, these should be seen as chance encounters with a low-value dataset, rather than indicative of possible improved performance. As has been mentioned, Genfis1 is only meant to provide a starting point for further optimization. Genfis2 and 3 perform very well, sometimes challenging the performance of NN or ANFIS algorithms, with the aforementioned caveat of possibly disastrous over-fitting. It should also be noted that, in the binary case, Genfis is greatly helped by being able to declare two, membership, function variables, which very nicely model the binary ones.ANFIS models performed very well throughout all tests and are the main contender of the neural network algorithms, which they oftentimes outperformed. The variation of their results was slightly higher than that of the neural networks, which is their only real disadvantage. However, given the inherent variation of results from different runs of the algorithms, it can be said that their performance is comparable and, in some instances, preferable, to that of the neural networks. Additionally, similar to neural networks and in contrast to some of the Genfis models, they do not seem to be significantly affected by over-fitting, even though they are constructed on rather complex structures.The elapsed times of the various algorithms are generally comparable, lasting in the range of a few seconds, with the exception of training neural networks under certain configurations. While less training time is always preferable, it is not a major factor for the selection of this model, since the envisioned applications do not require real-time performance. As more experimental data becomes available, the elapsed times will likely increase and future work will deal with improving the speed of all the algorithms discussed in the paper. As a final recommendation and conclusion of the results presented, both neural networks and ANFIS (type 2 and 3) models perform very well on both the training and test sets and could be used for implementation. Any further choice between these two architectures would have more to do with either personal preference or external requirements for an eventual expanded application.The studies on modelling the friction and wear of metallic surfaces for friction couples with linear contact between a thermoplastic material armed with short glass fibers (SGF) and steel are complex and outline the influence of input parameters specific to the tribological system  on the output parameters of the tribological system: The wear volume of metallic material and the depth of the wear material.Neuro-fuzzy modelling of the metallic surface characterization on linear dry contact between plastic material reinforced with SGF and alloyed steel proves that the friction force is not only dependent on the friction coefficient and normal load, as previously thought, but also on the sliding speed and the physical and mechanical properties of the materials, which has significant impact in the characterization of new industrial processes utilizing short glass fiber reinforced polymers.Using advanced statistical and optimization algorithms on a dataset obtained from the hardware simulation, the results of the research led to modelling a dependency between the various variables of interest involved in the friction process. The subject draws a growing interest from the research community with the advent of highly advanced, intelligent classification, and optimization and regression algorithms.This research focused on processing an experimental dataset on contact wear, with the aim of obtaining prediction models for the two variables of interest, wear depth, and wear volume. The data was obtained through experiments run on friction couples with linear contact using three different types of polymers on two different types of steel variants. Aside from alternating the materials used, the speed and pressure applied to them were varied under the same operating conditions. The data was pre-processed and coded for use with numerical learning algorithms. Since two viable coding options were found, both resulting numerical problems were treated separately. Various possible data fitting models were then investigated, including a baseline model for reference (linear regression) and different variation of possible considered structures (Genfis and ANFIS models). These models were then judged on their ability to fit the available data, as quantified by two standard error norms, calculated for each model. The end result is a comparison of the performance of the multiple prediction systems and a discussion of the various factors that influence these numerical results.The chosen models are to be implemented in future work and in any practical implementation in similar conditions for metallic surface characterization within the field of tribology, robotics, and with wide impact metallic surface characterization applications in the wear process, emphasizing the abrasive, adhesive, and corrosive wear. It will be of great interest to investigate the interaction of the current prediction models with real world applications for which there are many options ,11,12,27Another very important direction for further research focuses on gathering more experimental data to allow the development of even more complex enhanced models, either pertaining to new developments in the state of the art, or for retraining the current architectures. Over-fitting, an issue present and discussed throughout the work, should be greatly diminished with training on more available data. This is because most of the models do not over-fit out of design or implementation reasons, but simply because some are too complex  for the current dataset.


In 2005, the European Union (EU) started to use a disability-free life expectancy, known as Healthy Life Years (HLY), to monitor progress in the strategic European policies such as the 2000 Lisbon strategy. HLY are based on the underlying measure: the Global Activity Limitation Indicator (GALI). Twelve years after its implementation, this study aims to assess its current use in EU Member States and the European Commission.In March 2017, a questionnaire was sent to 28 Member states and the European Commission. The questionnaire inquired how the GALI and HLY are used to set policy targets, in which surveys the GALI has been introduced since 2005, how the GALI and HLY are presented, and what the capacity in each country is to investigate the GALI and HLY.The survey was answered by 22 Member States and by the Commission. HLY are often used to set targets and develop strategies in health such as national health plans. Analysis of HLY has even led to policy change. In some countries, HLY have become the main indicator for health, gaining more importance than life expectancy. More recently, the GALI and HLY have also been used for policy targets outside the health sector such as in the area of pension and retirement age or in the context of sustainable development. Regarding surveys, the GALI is mostly obtained from the EU-SILC, SHARE and EHIS, but is also increasingly introduced in national surveys. National health reporting systems usually present HLY on their national statistics websites. Most countries have up to three specialists working on the GALI and HLY, which has been consistent through time. Others have increased their capacity over various institutions.HLY is an indicator that is systematically used to monitor health developments in most EU countries. The SHARE, EU-SILC and EHIS are commonly used to assess HLY through the GALI. The results are then described in reports and presented on national statistics websites and used in different policy settings. Expertise to analyse the GALI and HLY is available in most countries.The online version of this article (10.1186/s13690-018-0279-z) contains supplementary material, which is available to authorized users. The development of the GALI occurred in the framework of the creation of a coherent set of indicators to monitor health across Europe [Health expectancies combine information on mortality and morbidity, where the quality of remaining life is as important as the quantity . Increass Europe . The GALs Europe . EurostaA HLY improvement is the main health goal of the EU in order to reduce the social and economic burden with life expectancy lengthening . The EurSince 2006, no assessment has been carried out to look at the use and uptake of the GALI and HLY in the EU. Despite the EU’s attention, the evolution of the GALI and HLY indicators has not been examined for over 10 years. This study aims to assess the current use of the GALI and HLY indicators by the European Commission and EU Member States. The aim was not to cover a representative sample of potential users, but rather to have a variety of respondents active in the field who could provide a picture of current uses in Member States and the EU.n = 2), statistical offices (n = 8), public health institutes (n = 8) and universities (n = 4) that are potential users. Two experts from the European Commission responded to the survey. After purposive sampling, snowball sampling was used. The respondents were asked whether they were the right contact person to respond to the survey. If this was not the case, the respondents were asked to provide contact details for a more suitable contact person and the survey was forwarded to this person. Out of the 30 contacted persons, 23 returned their questionnaire, one suggested other colleagues to be contacted. The questionnaire was sent by email in March 2017 and a reminder was sent after one month. One response to the questionnaire per country was aimed for to provide a picture of current use. Information was complemented with data available from the EHLEIS network and the literature.A questionnaire was sent to experts active in the European Health and Life Expectancy Information System (EHLEIS) project, or working in a relevant public health and/or statistical area, in 28 Member states and two departments of the European Commission , 10. InfThe questionnaire  or a statistical institute (n = 8), but other agencies such as ministries and universities were also covered with respectively two and four respondents. The non-responding Member States were Croatia, Ireland, Luxembourg, Malta, Poland and Portugal. Not all answers addressed the questions completely, however only 3 out of 144 questions were left completely unanswered.Twenty-two Member States responded to the questionnaire resulting in a 79% response rate in the Member States and two responded from the European Commission. The majority of Member States respondents were part of a public health institute  including DG Communication, DG Connect, DG Employment, DG Eurostat and DG SANTE Table . HLY areN = 2), the European health examination survey (N = 2), and various other surveys on health status, health care, living style, work, school health, housing, family resources, life opportunities, gender and social protection. In Belgium, the GALI is even used in small scale studies e.g. on Lyme disease. Negotiations between Eurostat and the EU Member States are ongoing to insert the GALI as a disability variable into the Labour Force Survey once every two years, thus creating a reliable monitoring tool on the employment of people with disabilities. The 2017 SILC module on children also includes a disability perspective (the GALI variable adapted for children), thus bridging the knowledge gap regarding children with disabilities in households.All participants reported that the GALI question was introduced in the EU-SILC. Some respondents did point out the wording had changed over the years since its introduction. Also in the European Health Interview Survey (EHIS) most countries have the GALI question included. Only Austria reported it had removed the GALI question from the EHIS. Eight countries indicated to have the GALI question in other national or regional surveys. Only two countries mentioned to have the GALI question in the Survey of Health, Ageing and Retirement in Europe (SHARE) in their country, even though the SHARE containing the GALI question is currently carried out in 16 EU Member States. Other Surveys mentioned by participants were the censuses (n = 11). In the Czech Republic, a special page is even allocated to HLY on the website of the Institute of Health Information and Statistics [Country reports are yearly produced by EHLEIS . In the atistics . In the atistics . Also inatistics . FinallyOne of the main tasks of the EHLEIS project was to increase the capacity to analyse HLY within the EU through training workshops and guidelines for estimation and interpretation of HLY . The EHLThe GALI and HLY are important measures to monitor progress in various policy domains. Since the last evaluation in 2006 , the useThe GALI question is institutionalised in most important health questionnaires through the MEHM such as the EU-SILC, the SHARE and the EHIS . This waHLY are presented in various reports. The country reports produced by EHLEIS are well received by countries and increase the uptake of HLY at national level as the reports are published on countries websites. This is important to improve the understanding of the concept in a unified way and to provide a yearly update. Furthermore, the presentation and dissemination of HLY are most prominent on national statistics websites. Some countries provide data analysis and conclusions on their HLY results increasing the visibility of the GALI and HLY. Other findings on HLY are presented in reports on the EU-SILC and EHIS. The capacity working on the GALI and HLY in the Member States has either remained unchanged or slightly increased over the years. The capacity is usually spread over various institutions being national public health institutes, statistics offices and universities.At the European Commission, HLY are reported in various health reports such as the Country health profiles and in Health at a glance: Europe report. Also outside the health domain, HLY are used in reports on social protection and inclusion as well as on disability and employment. The production and dissemination of HLY and the GALI follow already established procedures which confirm their institutionalisation, but has a decline in resources and capacity at EU – level as a consequence.Since only one respondent per country was aimed for in this study, due to resources constraints, the responses may have been incomplete and may not reflect a country wide perspective. Also, the results from the study demonstrated that the areas in which the GALI and HLY are used can be broad and the respondents may only be aware of use in certain areas. However, the respondents were chosen due to their active participation in the EHLEIS network and their expertise in the field. Therefore, they seemed to be suitable to respond to the questionnaire. Participants were also asked to provide another contact person if they did not know the answers to the questionnaire. Various respondents provided links to national reports and websites. Due to the language barrier not all reports could be assessed thoroughly.In ten years, there has been a real evolution in the use of the GALI and HLY. The use of the GALI and HLY are now widespread in Member States and in the European Commission and has, over the years, become institutionalised. The GALI and HLY are used for policy making , impact assessment , and monitoring . Additionally, HLY are increasingly being used to design policies and programmes. The GALI and HLY are not only used in the policy area of the health sector encompassing disabilities and healthy ageing, but have also gained importance in other fields such as retirement, budgets and sustainable development. The GALI is integrated in major health surveys which support its long-term sustainability. Although the capacity fluctuates between countries, most countries have capacity to evaluate the GALI and HLY. This analysis encourages further documenting for the policy makers how HLY and the GALI are measured and what type of interpretation can be driven from the secular or cross-country comparisons.Additional file 1:Survey on the use of the Global Activity Limitation Indicator (GALI) and Healthy Life years (HLY) in the Member States (MS) of the European Union (EU) and associated countries. (DOCX 16 kb)


A systematic review was conducted to investigate whether bilingualism has a protective effect against cognitive decline in aging and can protect against dementia. We searched the Medline, ScienceDirect, Scopus, and ERIC databases with a cut-off date of 31 March 2019, thereby following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. Our search resulted in 34 eligible studies. Mixed results were found with respect to the protective effect of bilingualism against cognitive decline. Several studies showed a protective effect whereas other studies failed to find it. Moreover, evidence for a delay of the onset of dementia of between 4 and 5.5 years in bilingual individuals compared to monolinguals was found in several studies, but not in all. Methodological differences in the set-up of the studies seem to explain these mixed results. Lifelong bilingualism is a complex individual process, and many factors seem to influence this and need to be further investigated. This can be best achieved through large longitudinal studies with objective behavioral and neuroimaging measurements. In conclusion, although some evidence was found for a cognitive reserve-enhancing effect of lifelong bilingualism and protection against dementia, to date, no firm conclusions can be drawn. The world population is aging, and this fact will have a large impact on healthcare systems . As a reDifferences between individuals in the way they are affected by brain damage or pathology have been reported in the literature. Individuals with more cognitive reserve were found to function better after the same amount of brain damage or pathology compared to individuals with less cognitive reserve ; this phNowadays, bilingualism is widespread, and the majority of the world population has been estimated to be bilingual ; moreoveIn addition to behavioral studies, neuroscience research has also focused on the possible link between bilingualism and cognitive decline at a neural level. Previous neuroscience studies have revealed that particularly the prefrontal and posterior  areas are involved in executive functioning , and thaThe aim of the present study is to provide an overview of the studies that have been conducted in the field of bilingualism and the protection of individuals against cognitive decline. Moreover, we are particularly interested in whether or not bilingualism can delay the onset of dementia. In a society with a growing number of old adults, finding factors that may protect individuals or delay cognitive decline and major neurocognitive disorders, such as dementia, is increasingly important . We expehttps://www.ncbi.nlm.nih.gov/pubmed/), ScienceDirect (https://www.sciencedirect.com/), Scopus (https://www.elsevier.com/solutions/scopus), and ERIC (https://eric.ed.gov/) databases with a cut-off date of March 31, 2019. We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol in our review study [We conducted a systematic review on bilingualism and the cognitive reserve hypothesis ,7. We weew study . We usedFour authors  independently searched the Medline, ScienceDirect, Scopus, and ERIC databases whereas four different authors  independently performed the study selection and data extraction. The selection of relevant studies was conducted based on previously determined inclusion and exclusion criteria. To be considered for inclusion, the study had to be published in a peer-review format. The extracted data consisted of the following information: the journal in which the study had been published, the authors and the title of the study, the publication year, the number of participants that had been entered into the study, the languages that were involved, the age of second language acquisition, the level of education (if available), and information about the exact methodology that had been used in the study. Note that in the present systematic review, we used a more inclusive definition of  cognitive reserve, meaning that also patient studies without direct measures of brain structure (that would determine the degree of damage or pathology) were included (we refer to the Discussion for a more detailed discussion of this issue). In cases of disagreement, four different authors  were asked to evaluate the study in question for inclusion in this review. In all cases, consensus could be reached among all twelve authors.As can be seen in *Please note that in order not to count one study twice, we decided to list the review study by Bialystok and colleagues  here.As can be seen in We first present the results that were found in studies investigating the relationship between bilingualism and cognitive decline in healthy individuals a. Kavé a1‒42 and phosporylated-tau/Aβ1‒42). The researchers used a wide range of neuropsychological tests [In addition to behavioral assessments, other measurement techniques are increasingly being used. Estanga and colleagues , for insal tests ,74,75,76al tests  conducteal tests ,54. Bialal tests  concludeIn contrast to the previously discussed studies, not all studies found evidence for a protective effect of bilingualism against cognitive decline. Crane and colleagues , for insSo far, we have presented studies that investigated the relationship between bilingualism and cognitive decline in healthy individuals. In the next part of our paper, we will focus on individuals that suffer from dementia. The questions that we are interested in are: Is bilingualism a cognitive reserve factor? Can bilingualism delay the onset of dementia in bilingual older adults? As can be seen in 18F) positron emission tomography (PET) study. The results showed that bilingualism is likely to contribute to cognitive reserve. Bilingual patients showed substantially greater impairment of glucose uptake in frontotemporal regions, in parietal regions, and in the left cerebellum than monolingual patients, indicating that in the early stages of AD, bilingual patients can compensate for more severe cerebral impairments than monolingual patients [18F) PET study as well in their investigation of brain metabolism and neural connectivity in bilingual and monolingual patients with probable AD. The results showed an increased connectivity in the executive control and the default mode networks in the bilingual patients as compared to the monolingual patients. Moreover, the study revealed that the degree of lifelong bilingualism  was significantly correlated to functional modulations in crucial neural networks. Perani and colleagues [The cognitive reserve-enhancing effect of lifelong bilingualism was also confirmed in neuroscience research ,47,49. Slleagues ,31,44 anlleagues ,57,58,60However, not all studies found evidence for a cognitive reserve-enhancing effect of lifelong bilingualism in older adults. Clare and colleagues , for insA systematic review was conducted to provide an overview of studies that had been conducted in the field of bilingualism and the protection of individuals against cognitive decline. We were particularly interested in whether or not bilingualism can delay the onset of dementia. In a society with a growing number of old adults, finding factors that may protect individuals against or delay cognitive decline and dementia is increasingly important .Firstly, we expected to find that bilingualism can protect individuals against cognitive decline. The results showed that, indeed, evidence exists for a cognitive reserve-enhancing effect of lifelong bilingualism ,38,48,50Secondly, we hypothesized that bilingualism can delay the onset of dementia. Patient studies on dementia showed evidence in favor of delaying the onset of symptoms of dementia, on average, for 4 to 5.5 years in older bilingual patients as compared to monolingual patients ,39,44,52Why are the results from studies on the relationship between bilingualism and cognitive reserve and the onset of dementia so heterogeneous? As can be seen in Neuroscience offers special tools and assessments to investigate the possible relationship between bilingualism and cognitive reserve. In contrast to behavioral studies, neuroscience makes possible direct investigation on aging individuals of neural, cellular, and molecular mechanisms in the brain that may underlie differences in behavioral results. A number of brain areas known to be involved in executive functioning circuits  seem to The frontostriatal and frontoparietal executive functioning networks, and their underlying cellular and molecular mechanisms, need to be investigated further in order to gain insights into the cognitive reserve capacity of the aging brain and the possible contributing factor of lifelong bilingualism. In this respect, future neuroscience research with repetitive transcranial magnetic stimulation (rTMS) and with transcranial direct current stimulation (tDCS) seems to be promising for shedding more light on the possible protective effect of bilingualism against cognitive decline in the aging brain  because Several methodological limitations exist in the research on the protective effect of bilingualism against cognitive decline and major neurocognitive disorders. Researchers point out that many factors see  can inflMoreover, researchers investigating the protective effect of bilingualism against cognitive decline and major neurocognitive disorders often use the analysis of covariance (ANCOVA) in the statistical analysis of their results. However, as Paap and colleagues  discusseAnother limitation of the present study  has to do with the concept “cognitive reserve”. There is a lack of consensus in the field regarding the exact definition of “ cognitive reserve”, and what  evidence is needed to determine its existence and degree. So far, most of the studies examining the relationship between bilingualism and cognitive functioning do not include measures of brain structure that would determine the degree of damage or pathology. That is, studies that are included compare bilingual to monolingual (patient) groups on measures of cognitive function  or age-of-onset of dementia, but in most studies, we do not know if there are concomitant differences in brain structure. Even if neuroscience measurements are used it is still unclear what  evidence is required to confirm the cognitive reserve hypothesis.The present study makes clear that future studies on several methodological issues are warranted before any firm conclusions on the protective effect of bilingualism against cognitive decline and dementia can be drawn. For instance, future research is needed on the issue of early versus late bilingualism and how this affects functional connectivity in the brain . In ordeMoreover, future studies are needed to address whether or not the language family  matters The majority of studies on the cognitive reserve-enhancing effect of lifelong bilingualism so far have focused on AD  ,39,44,49Additionally, gender differences may exist in the cognitive protective effect of lifelong bilingualism, as previous research discovered gender differences in healthy elderly individuals and in patients with AD . In a neAnother important issue warranting more research is the relationship between multilingualism, as opposed to bilingualism, and protection against cognitive decline and protection against or delay in the onset of dementia . DiffereBecause of the large variability in methodology between the existing bilingualism studies on older adults and patients  and the Another limitation of the present study is that we relied on the conclusions that were drawn by the authors to determine if a result favored the cognitive reserve-enhancing effects of bilingualism, partly supported that hypothesis, or if there was evidence against it. However, according to Paap and colleagues , there iFurthermore, with the specific key words we used  we had a clear focus on the cognitive reserve hypothesis . However, with other key words we would have perhaps been able to include other studies looking at the bilingual advantage in older adults in general. This less narrow approach would have resulted in a larger number of studies and in more negative results than the mixed results that were found in the present systematic review .Finally, patients with dementia and their families suffer from many problems and much pain ; moreoveWe found some evidence for a protective effect of bilingualism against cognitive decline in aging, but the results are mixed. Several factors, such as immigration and individual experiences, seem to affect the extent of the cognitive reserve-enhancing effect of lifelong bilingualism. Moreover, several studies reported delayed onset of dementia in bilingual individuals, but again, the results are not clear. Research groups often use different experimental tasks to assess cognitive functioning in healthy older adults and in patients with dementia; therefore, replication studies are warranted with the same methodology to make direct comparisons of the results among research groups possible. Lifelong bilingualism is a complex individual process, and many factors seem to influence this and need to be investigated further in large longitudinal studies with objective behavioral and neuroimaging measurements before the cognitive reserve-enhancing effect of lifelong bilingualism and the protection against dementia is proven.


This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a society that is confronted with an ever-increasing number of antibiotic-resistant bacteria, we build on the previously made recommendations and specifically address how the Nagoya Protocol might impact the further development of bacteriophage therapy. By reviewing a number of recently conducted case studies with bacteriophages involving patients with bacterial infections that could no longer be successfully treated by regular antibiotic therapy, we again stress the urgency and significance of the development of international guidelines and frameworks that might facilitate the legal and effective application of bacteriophage therapy by physicians and the receiving patients. Additionally, we list and comment on several recently started and ongoing clinical studies, including highly desired double-blind placebo-controlled randomized clinical trials. We conclude with an outlook on how recently developed DNA editing technologies are expected to further control and enhance the efficient application of bacteriophages. The history of antimicrobial drug discovery includes more than 15 classes of compounds that became a cornerstone in microbial infection control and management and have indisputably saved many lives . The extIn view of this alarming situation, we published a first opinion paper as a multidisciplinary expert group on the acceptance and re-implementation of bacteriophage therapy in 2016 . In thisFour issues have been identified that are limiting, or even preventing, the application of the bacteriophage therapy in the Western World in the 21st century : (1) Quahttps://clinicaltrials.gov/. Notwithstanding the increase in conducted trial numbers, the number of fully-completed and well-documented trials still remains too low to draw substantial conclusions for the diverse range of medical applications where bacteriophage therapy might be implemented. Of the completed trials, several factors have hampered their ability to conclude on the potential efficacy of phage therapy. Bacteriophage therapy has been used for more than 100 years, mainly in Eastern Europe. However, the number of double-blind, placebo-controlled, randomized clinical trials in different fields of medical applications have been limited. Furthermore, they fall far from providing statistically-relevant conclusions about the efficacy of bacteriophage therapy. As a consequence, health authorities and medical professionals in the Western World have been hesitant to proceed with the bacteriophage therapy. Escherichia coli diarrhea also did not reach their estimated patient numbers, because of early trial termination [Streptococcus sp. may have been a better clinical target than as initially anticipated, E. coli.Small patient cohorts and the failure to recruit enough patients have severely limited the conclusions that can be drawn from modern bacteriophage trials. For instance, the recently completed Phagoburn trial, which represented a public investment of 3.85 million euro, enrolled a total of only 27 patients between 11 centers . This wamination . An in-dThese two studies, which represent the largest in recent history, highlight several lessons to be learned for future bacteriophage therapy investigations. In addition to individual patient safety, ethical committees should also consider the overarching purpose of clinical trials to produce significant and generalizable results when reviewing clinical trial protocols; the inability to do so is both a detriment to the well-being of society and a waste of trial-eligible patients. Priority should be given to infections with established pathogens, and the test product should reflect the clinical reality to cover indicated pathogens. There is no clinical evidence to suggest a safety concern for targeting multiple pathogens with broad spectrum bacteriophage products, as supported by several recent clinical trials , the PolGiven the time and financial investment required for clinical trials, it might be prudent to exploit information from smaller-scale clinical investigations, as well as the ongoing practice of bacteriophage therapy in Eastern countries. Valuable knowledge to understanding bacteriophage therapy has already been generated by The Polish bacteriophage Therapy Unit at the Hirszfeld Institute, a nonprofit entity, that has accumulated data from years of individual patient reports . Good inToday’s legislation and safety requirements for the production and admission of drugs are, for good reasons, heavily controlled. By having strict quality control procedures, it is assured that drugs are effective, safe, and produced with a consistent quality and composition. The production and application of bacteriophage therapy should not be any different. However, the nature of bacteriophages and their effective medical application are not compatible with current production and admission requirements for chemical drugs. The intrinsic strength of bacteriophages relates to their antagonistic evolution with their bacterial hosts. To assure an effective application of bacteriophage therapy, this requires the ability to continuously adjust and adapt the composition of bacteriophage cocktails. Such a flexible and dynamic production system, coupled with the application of an infection-eliminating medication is incompatible with current legislation and safety requirements set for traditional static and chemically produced drugs. Although the use of bacteriophages is already quite old, in fact, their tailor-made use and applications are in line with the growing demand and insights around personalized nutrition and personalized medicine, where DNA, microbiome composition, and personal lifestyle act as leading indicators. Previously, we referred to a couple of proposals to overcome this incompatibility with today’s regulatory frameworks in the Western World, while still assuring safety and efficacy . For insRegarding good manufacturing practices, experts are in agreement that these should be defined in the specific context of bacteriophages as natural entities. The use of whole genome sequencing technologies, together with several additional specific controls , can assAnother suggested mechanism that was highlighted by the panel members to ensure the safety of bacteriophage therapy relates to the implementation of a monitoring system. This would function much like that for antibiotic resistance, and should be put into place as soon as bacteriophage therapy has started. The main purpose of the monitoring system is to collect data for prospective analyses, as well as to detect and follow the development of bacterial resistance to bacteriophages. Several researchers have made proposals for the safe re-implementation of bacteriophages by establishing validated bacteriophage collections in hospitals for compassionate use applications. In this way, as soon as the bacterial pathogen has been identified, which is often practiced already, it could be tested for sensitivity against such a library of bacteriophages . AnotherFor many years, the history and potential of bacteriophage therapy was out of sight for people in the Western World, including medical staff and patients. Following the international increase of antibiotic resistance of pathogens and since the 100th anniversary of bacteriophage therapy in 2017, there has been a clear increase in reporting and communication on bacteriophage therapy in all forms of media in many Western countries, including scientific opinion articles, television programs, and social media initiatives. Also, the increase of medical tourism to Georgia or Poland for bacteriophage treatment illustrates a growing awareness on and demand for bacteriophage therapy. Despite this increase of public awareness, panel members feel that there is still not enough interface with the medical community. Little focus is given in the curricula used for (para-) medical trainees on phage therapy, including bacteria-phage antagonistic evolution. Expertise on phage therapy could easily be provided through researchers who by reaching out to their medical colleagues operating at local hospitals. In this way, relevant information can be disseminated about the pros and cons of bacteriophage therapy in the context of the emergence and spreading of antimicrobial resistance. The increased awareness could thus lead to more application of bacteriophages for compassionate use as described above. At the same time, hospitals and patients should be aware that bacteriophage therapy will not always be successful and yet unknown safety risks and complications cannot be excluded.Bacteriophages are ubiquitous natural organisms that are relatively easy to isolate from the environment and have been in the public domain since the 1920s, and therefore the possibilities for intellectual property (IP) protection are limited. Although this might be seen as a limitation by companies intending to seriously invest in bacteriophage therapy, in fact it also offers the opportunity for local, national, and supra-national state-supported medical care to collectively invest in the development of bacteriophage therapy that is expected to be more cost-effective for treatment of many infectious diseases compared to several of the currently used antibiotics. The expected efficacy and affordability of bacteriophage therapy is also illustrated by initiatives around development of bacteriophage therapy in developing countries. In these situations, people are disproportionately impacted by infectious diseases, leading to a critical disease burden on healthcare budgets, and where standard medical care is already difficult to afford for the majority of the population . We expect IP protection opportunities to exist for bacteriophage production methods, as well as for applications that can enhance the efficiency and quality of bacteriophage therapy, and/or improve shelf-life stability. Opportunities to protect IP will also come from genetically-engineered bacteriophages, as outlined further in this article. In addition, we see options for private/government partnerships with patent pools under supra national governance that should be managed through organizations such as the WHO, CDC, ECDC or UN .In order to increase acceptance and implementation of bacteriophage therapy, it is obvious that rapid and efficient procurement of bacteriophages from the environment with therapeutic potential, and their bacterial hosts, is essential. Bacteriophages, along with all other genetic  resources, are regulated by the Nagoya Protocol (NP). Briefly put, this means that regulations governing the collection of bioresources from natural environments and subsequent benefit-sharing with the country of origin are increasingly important . 7 bacteriophage particles might be present in any one milliliter of natural sample. As a result, thousands of new genetic resources can result from a single step of sampling from the environment, but there are thousands of diverse natural environments around the world that are not limited to one specific country or region of interest. New environmental samples are themselves inherently worthless, as the potential for each bacteriophages and bacterial isolates is unknown and intensive research is necessary to purify and evaluate these characteristics. Additionally, high numbers of specific bacterial hosts are required for phage amplification, to determine the activity spectrum, and to increase their efficacy in clinical applications. Taken together, these scientific realities mean that researchers will be likely to search for bacteriophages/hosts where NP restrictions are either not in place, or where the NP highly efficiently organized. In 2017, several authors evaluated the impact of the NP on research and international cooperation, the need for best practices for benefit-sharing, and proposed adjustments to the NP to accommodate microbiological research and development (R&D) ,4. SinceE. coli O104:H4 EAHEC that caused more than 50 cases of deaths), the NP might impede progress in the global search for potent therapeutics and straightforward exchange of bacteriophages that could save lives.Bacteriophages offer great potential for human and veterinary medicine, but NP regulations could be interpreted as in conflict with the WHO objective (and subsequent G7 and G20 summits) calling for all countries to develop alternative antibacterial strategies in human medicine . Also inFor microorganisms in general, and for research and applications of bacteriophages in particular, we share the concerns put forward in the Lactic Acid Bacterial Industrial Platform (LABIP)  and MicrBox 1www.cbd.int), which itself has been in force since December 1993, and is intended to harmonize access and benefit-sharing mechanisms for the retrieval of biological resources out of provider countries (often in emerging economies). The purpose of the NP is to achieve the objectives of the CBD: 1. Conservation of biodiversity, 2. Sustainable use of the genetic resources and 3. Balanced and equitable sharing of benefits when genetic resources are used (Access and Benefit Sharing (ABS)). Hereto, before starting any research and development work on biological resources, Prior Informed Consent (PIC) by the ‘provider country’ is needed, which done according to Mutually Agreed Terms (MAT) to be laid down in a contract describing access to the materials and how benefits will be shared. In practice, benefit sharing can take a variety of forms, including monetary payments, for example with royalties or research funding, but also via non-monetary forms, such as technology transfer or scientific collaborations. Historically, bioresources were considered a shared heritage of humankind, and the NP allows signatories to regulate access to genetic resources to ensure benefit-sharing with such provider country. Generic guidance flowcharts are given by Overmann and Scholz [The NP is a new international regime that came into effect on 12 October 2014, and has been ratified by more than 100 countries. The NP is the implementing treaty for the Convention on Biological Diversity , which provides country profiles and, if appropriate, national regulations that, ideally, explain how to access their sovereign genetic resources, including required documents such as PIC and MAT. Due to the current lack of completed country profiles in the ABSCH, it is often difficult to find the practical information needed to be compliant with the NP. The long-term implications for phage research are unclear, but conceivably threatened.Within the EU, member states are varied in the regulation of access to genetic resources, with northern Member States often allowing unrestricted access and southern States considering regulation. The United States neither ratified the CBD nor the NP, but these international agreements do affect U.S. scientists and aligned standard operating procedures are in development . The priE. coli, due to the range of editing strategies already developed for this model bacterium. On the contrary, CRISPR/Cas-editing can be applied also to bacteriophages targeting members of the ESKAPE pathogen group . This has already been proven in Staphylococcus aureus and bacteriophage ISP [Kayvirus as a bacteriophage used in the EU-approved therapeutic STAFAL®. Thus, previously proposed applications of genetically-engineered bacteriophages are expected to get relevant clinical significance as summarized in In the era of gene editing, it is relevant to study the potential of genetically-modified bacteriophages as therapeutics. Bacteriophages could be engineered for better efficacy and a broader range of application, and, importantly, would be more attractive for investors due the generation of IP rights (see above). Recent advances in CRISPR/Cas-editing see  made bachage ISP , which iE. coli, ii. type II-A, which requires only one protein Cas 9 and sgRNA for editing ability and is best described so far, and iii. type III-A, which does not require a protospacer adjacent motive and cannot be evaded by simple nucleotide substitution [Seven bacteriophages from various hosts have recently been successfully edited using three different types of CRISPR/Cas : i. typetitution .Box 2CRISPR/Cas  was originally identified as a prokaryotic adaptive immune system. It mediates the cleavage of foreign DNA by Cas nuclease if this DNA matches the sequence of spacers in the CRISPR locus. It soon became an important method for eukaryotic genome engineering. However, a limited number of studies have been concerned with its application in bacterial genome engineering due to the poor ability of bacteria to repair CRISPR/Cas-induced breaks . BacteriOne of the unknowns concerning CRISPR/Cas-edited bacteriophages relates to whether the mutations will be preserved and reproduced, or if spontaneous mutants that escape the CRISPR/Cas will arise and, due to increased fitness, will outgrow the recombinant. As a consequence, bacteriophages with many point mutations in inserted foreign genes and tags would emerge, rendering the intended modifications useless. A solution could potentially come through the application of CRISPR/Cas III-A, where there has been no evidence of escape mutants . HoweverCRISPR/Cas-edited bacteriophages with heterologous gene insertions would rank as genetically modified organisms (GMOs), which brings additional hurdles to their approval as therapeutic agents. Their future success will therefore depend on the safety and environmental regulation of GMOs in individual countries. At present, the United States and China appear to have far more amenable policies and prospects for GMO acceptance compared to the EU and Russia. The reproducibility and viability of a genetically modified bacteriophage could also be eliminated by introducing lethal mutations to ensure that the modified bacteriophage would disappear over time, therefore decreasing environmental concerns. Another option is to transform the bacteriophage to a non-replicative delivery vehicle that would mediate killing by an alternative approach , which iBox 3Apart from editing, CRISPR/Cas has been utilized as a weapon for the specific killing of virulent or antibiotic-resistant bacterial strains, by reprogramming CRISPR/Cas to target a gene sequence encoding such a property. A bacteriophage can serve as a delivery vehicle, by binding to the relevant bacterial strain and transferring DNA encoding Cas9 nuclease and sgRNA into the cell. This DNA is packaged into the bacteriophage capsids by introduction of specific bacteriophage packaging sites on both ends of the sequence. As a result, only the targeted strain is eliminated, therefore preserving the rest of the microbiome. In addition, the transfer of the undesired phenotypic traits is abolished among strains infected by the delivery bacteriophage. Many groups are studying this strategy , with sDespite the absence of adverse reports and also the recent progress and resulting knowledge in the area of natural bacteriophage immunogenicity , the mecGiven the continuous need for propagating host strains, the probability of survival of bacteriophages, including modified bacteriophages, outside the laboratory or hospital is minimal. However, the risk of recombination between modified and wild-type bacteriophages or horizontal gene transfer among modified bacteriophages and bacteria must be evaluated, particularly in case bacteriophages would carry genes foreign antibacterial products. Theoretically, uptake and incorporation of such sequences by a bacterium may result in a fitness advantage over the strain for which the bacteriophage was originally designed. The urgent need for effective alternatives to antimicrobials is self-evident in order to reduce the morbidity and mortality associated with antimicrobial resistance, as well as reducing the healthcare burden on economies. Many proposals have been made on which path bacteriophage therapy should follow in order to be approved. A recurrent conclusion is that this therapy will never become a viable option if we continue assessing this treatment under the same regulatory frameworks as for chemical drugs. In fact, bacteriophage therapy is already safely being applied today, as demonstrated not only from ongoing activities in Eastern Europe, but also from the observation that already for more than a decade several of the successful bacteriophage therapy cases reported in the Western World  are led If bacteriophage therapy is to develop as a means to stop the emergence of antibiotic resistance, courageous decision making is needed that allows the controlled use of bacteriophage. This needs to take into consideration the many years of practice in Russia, Georgia and Poland, and which is in line with many good proposals from scientists and physicians who understand the specific nature of bacteriophages. At the same time, we should not expect that bacteriophage therapy will always be 100% effective and might occasionally induce side effects, as we will understand better upon the implementation of bacteriophage therapy monitoring systems. But how does the occurrence of potential side effect compare to the opportunity costs of not applying bacteriophage therapy in case of antibiotic resistance? Furthermore, also for antibiotics that in many cases are lifesaving, we accept undesired side effects, for instance when due to the unspecific mode of action of antibiotics beneficial microbes are also affected, which often causes complications such as antibiotic-induced dysbiosis and secondary infections. A great step forward can be made when more countries will follow the example of the Belgian Ministry of Public Health regarding the set- up of a phage therapy framework that centers on the magistral preparation (compounding pharmacy in the US) of tailor-made phage medicines. Importantly, this Belgian solution assures safety and avoids the application of certain medicinal product requirements that restrain flexible phage therapy approaches, such as compliance to Good Manufacturing Practice . In this paper, we have underlined the call for more RCTs with bacteriophage therapy. In this context, it is also an important responsibility of the researchers involved to properly report the outcome of the studies, as has not always been the case . IncomplWith regard to the Nagoya Protocol, we call for pragmatic approaches to obtain Prior Informed Consent (PIC) and Mutually Agreed Terms (MAT) that are proportional to the value of the immediate foreseen benefits. Otherwise, due to the delays that might be encountered in the process, there may not be any significant benefit to share. Since there are, at present, very few culture collections with bacteriophage holdings, new bacteriophages have to be isolated in high numbers to constantly fulfill the WHO resolution 68.7.3 (WHO Assembly October 2016). The proposed amendments and clarifications to NP as mentioned in the section on NP could facilitate that the protocol does not unintendedly retard these innovative developments that are important for humankind in the 21st century. This is especially valid for a rapid and effective application of bacteriophages in the events of emergency since users should ensure legally-complied uses of the genetic resources, including those for collaborative projects. While it becomes increasingly acknowledged that bacteriophage therapy, as applied already for many years in some countries, has great potential to combat the consequences of increasing antibiotic resistance, we acknowledge that the traditional bacteriophage therapy also has some limitations. In this article, we have described that the use of CRISPR/Cas to specifically edit the genome of natural bacteriophages offers an opportunity for controlled and effective bacteriophage therapy and may facilitate reliable future applications of the bacteriophage therapy. However, today several technical issues and safety concerns of GM bacteriophages still need to be addressed. The first step would be to prove that modified bacteriophages could be prepared in large-scale, without any significant background of undesirable mutants. Next, research should focus on immunogenicity assessment of modified virions and potential horizontal transfer of genes encoding antibacterial products. We expect that in a time frame of five-to-ten years, it will become clear if this approach for bacteriophage therapy is worthwhile. Furthermore, it is foreseen that CRISPR/Cas-edited bacteriophages will revolutionize bacteriophage therapy, if not by direct application of modified bacteriophages, by the enormous possibilities that it will bring to fundamental research on bacteriophage biology.Although the entire world seems to agree on the clear urgency to implement novel solutions, it is worrying to see that therapy with natural bacteriophages has yet to be seriously considered in the Western World. Notwithstanding some open questions, there are many realistic options and scenarios that would enable a gradual, pragmatic, and responsible re-implementation of bacteriophage therapy in the short term to help avoid needless deaths due to antibiotic-resistant infections. Any further delay could be seen as a supported prolongation of the difficult conditions many patients without alternative treatment options find themselves in today.