For the efficient and safe production of pharmaceutical tablets, a deep process understanding is of high importance. An essential process step during tableting is the die filling, as it is responsible for a consistent tablet weight and drug content. Furthermore, it affects the results of subsequent process steps, compaction and ejection, and thus critical quality attributes. This study focuses on understanding the influences of process parameters and material properties on die filling on a rotary tablet press. By the systematic variation in process parameters as the turret and paddle speeds as well as the fill and dosing depths, five formulations with differing properties are processed. Analysis of the normalized tablet weight, called filling yield, revealed different limitation mechanisms of the filling process, i.e., incomplete filled dies for certain parameter settings. Kinetic limitations occur due to a short residence time under the feed frame (filling time) caused by high turret speeds, which additionally induce high tablet weight variation coefficients. Characteristic maximum turret speeds at certain paddle speeds can be found to still achieve complete filling. At low turret speeds, densification of the powder inside the dies takes place, induced by two mechanisms: either high paddle speeds or high overfill ratios, or a combination of both. The challenge to fill the dies completely as well as avoid densification is dependent on material properties as the flowability. The mass discharge rate from an orifice was found to be in a linear correlation to the filling results of different formulations below complete filling. In the pharmaceutical industry, deeper process understanding is gaining importance. This is emphasized by the Quality by Design (QbD) approach promoted by health authorities . In the The tableting process can be divided into four steps: powder feeding, die filling, compaction and ejection. The product quality fundamentally depends on die filling. It critically affects the tablet quality, as weight variations contribute to drug content variations. Furthermore, subsequent process steps such as compaction and ejection depend on the result of filling. If die filling is not accurate, the effective pressure acting on the powder bed, applied by the opposing punch movement, undercuts the processing limits. Thus, quality attributes like tensile strength, porosity and dissolution behavior can be influenced. To meet the required quality, it is necessary to ensure a complete, reproducible and consistent die filling.gravity filling, suction filling and forced feeding [Gravity filling occurs for powder flowing into a die cavity under gravity [Suction filling takes place due to an arising pressure gradient from the downward movement of the lower punch under the powder bed inside the feed frame, pulling the powder into the die cavity. Furthermore, improvement in the filling process is achieved by feeding systems with moved components, referred to as forced feeding.Different mechanisms have been identified for die filling, which involve  feeding . Gravity gravity . Suctionpaddle feeder. In the most common two-wheel setup, the first wheel, called the feeding wheel, delivers powder into the die while the second wheel, the metering wheel, transfers the exceeded powder back into the feed frame. In some constructions, a third wheel is positioned in the center above the feeding and metering wheel to supply powder equally to both wheels [Industrial rotary tablet presses commonly use a forced feeding system consisting of a feed frame equipped with one to three stirrers, called h wheels .forced feeding, suction filling and overfilling as well as disruptive factors like centrifugal forces, vibrations and vertical stress caused by the above powder, acting simultaneously in a rotary tablet press, result in a complex process [The dosing depth results from the fill depth, which is defined by the fill cam, minus the overfilling height, which is used to support complete die filling . Thus, a process . Variablgravity fill in air and vacuum to investigate the flow properties of pharmaceutical powders to try to resemble die filling on a rotary press [suction fill, which can take place in a rotary press, was detected by Jackson et al. [gravity fill equipped with moved dies and a stationary feeder, mimicking a rotary press more realistically, was used to correlate die filling performance and critical material attributes [Several studies were carried out to understand the filling process using a linear filling device ,10,11,12n et al. ,22,23,24tributes . Furthertributes ,27. Withtributes ,20,21,22Although there were several research studies describing the filling efficiency, these simplified systems are able to investigate effects of selected parameters, but often important parameters were not taken into account, which is why the general transfer of findings is limited . There aIn contrast, Peeters et al. investigated the influence of turret speed, paddle speed, fill depth and material properties with a Design of Experiments (DoE) by using microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate (DCP) directly on the rotary tablet press MODULE™ P (GEA) . The intDue to the lack of deep understanding, the aim of the current work was to systematically investigate the influence of particular process parameters and powder properties to achieve an improved understanding of the mechanistic relations regarding tablet weight and weight variation. This is performed directly on a rotary press to avoid differences in operating modes that may finally hinder the transferability of models from testing rigs to industrially relevant machines and processes. The findings should also be transferable to other powders and formulations.® 102, JRS Pharma, Rosenberg, Germany) and anhydrous dicalcium phosphate  were used as model materials. Magnesium stearate  was used as a lubricant. The characteristic particle sizes of MCC and DCPA are in a comparable range with slightly lower particle sizes for MCC . Three measurements were performed, and the mean values were calculated. The solid densities of the powders were measured in triplicate with the helium pycnometer Ultrapyc 1200e . The bulk and tapped density were determined according to the Ph. Eur. 9.3 2.9.34 using a 100 mL cylinder, tapped by a volumetric analyzer . Measurements for each sample were carried out in triplicate, calculating the average. Based on the bulk and tapped density, the Hausner ratio The three blends of MCC and DCPA were prepared using a cube mixer . The volume of 3.5 L was filled up to 40%. Initially, DCPA was mixed with 1 wt % magnesium stearate (MgSt) for five minutes at 30 rpm, then MCC was added and mixed for another ten minutes. The composition of the three blends processed on the XL 100 are displayed in n = 10) . For the investigation, a paddle feeder with one wheel—the feeding wheel—was used. The press was equipped with four flat-faced round Euro-D punches with a diameter of 9 mm. No external vacuum cleaner for aspiration was used. In order to investigate the influence of different fill depths, three fill cams with fill depth of 10, 14 and 16 mm were used; the corresponding dosing depth and operating speeds can be found in Die filling/tableting experiments were carried out with the rotary tablet press XL 100  in lab scale. Therefore, tablets were produced at different process parameters, determining their weight afterwards as a measure for the filling weight ).Different dosing depths as well as powders with different bulk and tapped densities, normalization is necessary to allow the comparison of the resulted tablet weight as the dimensionless result of filling. Therefore, the filling yield φ is defined as the ratio of the tablet weight Tm to the theoretical maximum weight resulting from the dosing volume inside the die, calculated with the die radius dier and the Ddosing depth h, as well as the tapped density tρ of the respective powder (Equation (5)).Regarding different The tapped density is used due to the assumption that maximum powder consolidation in the feed frame and during die filling is comparable to the impact of the taps, which leads to the greatest change in particle packing in normal direction due to the powder weight. For this reason, it is hypothesized that the tapped density can be used as a limit for consolidation inside the die without compaction, and accordingly the maximum filling yield amounts to 1.bρ to the weight resulting from the dosing volume filled with tapped density, called unconsolidated complete die filling UCF (Equation (6)). The equation can be simplified to the ratio of bulk density to tapped density which equals the inverse of the Hausner ratio.Corresponding to the consolidated state, a reference value for complete die filling in the unconsolidated state, related to the bulk density, can be defined. Therefore, the filling yield represents complete die filling for the ratio of the weight resulting from the dosing volume filled with bulk density tablet weight variation coefficient WVC which equals the relative standard deviation (Equation (7)). It is calculated as the percentage of the standard deviation of the mean value of the filling yield.The variation in the filling yield is described by the For a better understanding and explanations of the following experimental data, the filling process is described in detail. Die filling can be divided into four process steps. The area in which the respective process step takes place is marked with the abbreviations in a schematic overview with plan view :PS1—powder feeding from the hopper into the feed frame;PS2—powder transport by the feeding wheel (into the filling area);PS3—die filling;PS4—dosing out: reduction of die fill volume  and the paddle speed. Thus, in the following, general understanding of the impact and interplay of each process parameter is investigated based on the most extreme formulations of MCC and DCPA. As the blends show results between the pure substances, they are not displayed separately in this section. The influence of the material properties of the blends is investigated and discussed in The turret and paddle speed, as the dynamic parameters of the system, simultaneously influence the die filling by their interaction. The turret speed is directly linked to the tablet production rate , which iunconsolidated complete die filling (UCF) in order to compare the actual filling yield with the complete filling at an unconsolidated state. For MCC, one can observe that only at low turret speeds of 20 and 30 rpm, and in parallel high paddle speeds of 40 and 60 rpm, UCF is achieved . On the contrary, at the parameter setting displayed, MCC does not show densification above UCF but asymptotically reaches the UCF, indicating that no consolidation by dynamic parameters was achieved for MCC for this case.As the graphs for DCPA show filling yields above In general, one can find a minimum paddle speed at a certain turret speed to overcome the kinetic limitation and to fill the dies completely. The higher the turret speed and the poorer the flow properties of the material, the higher the minimum paddle speed needs to be. An increasing paddle speed has a considerably higher impact on the filling yield of fairly flowing (MCC) compared to free-flowing powders (DCPA).tablet weight variation coefficient (WVC) is a crucial factor for tablet production. It is important to gain reproducible tablet weights to ensure constant drug content. The WVCs of MCC and DCPA show strong differences as function of the turret and paddle speeds  at a fill depth of 16 mm are presented for MCC a,b,c andUCF rise with increasing paddle speed. For MCC at 20 rpm turret speed . Furthermore, at higher paddle speeds, additional powder may be above the die during dosing out, acting as a resistance against powder ejection and leading to densification as well (PS4). As MCC has a higher compressibility based on the Compressibility index compared to DCPA ).Densification due to the overfill ratio is presented in For the slope, one can observe hyperbolic courses over the mass content of DCPA at both paddle speeds for all fill depths. MCC provides considerably high slopes, while the values decrease drastically with increasing DCPA content. A high positive slope indicates a strong impact of the overfill ratio on the apparent density inside the die. Unexpectedly, the slopes of the blends are almost as low as for DCPA, which does not correlate with the Compressibility index . TherefoFor the two paddle speeds of 20 and 60 rpm, no considerable and systematic differences can be observed. The courses for fill depth of 14 and 16 mm are in good accordance, while, at 10 mm fill depth, the values for the slopes differ slightly. For MCC and the blend with 25 wt % DCPA, lower slopes are found, while the slopes for DCPA and the blends with a higher DCPA content are slightly higher. This indicates a higher impact of the overfill ratio at low fill depth. However, this can be related to the increased fill level inside the feed frame for free-flowing powders, which is assumed to be higher with lowering dosing depths. Thus, the higher slope might be due to an increased apparent density inside the die and probably in the feed frame during filling or because of the increased resistance against powder ejection during dosing.UCF is displayed to compare the data to the status of unconsolidated filling.The axis intercept, investigated at paddle speeds of 20 and 60 rpm, provides information about the theoretical apparent filling yield inside the die at an overfill ratio of zero, so no volume reduction takes place. Thus, the influence of other process parameters, as the paddle speed, on the densification is observable. Besides the data for the axis intercept at the paddle speeds of 20 and 60 rpm, the For the axis intercept of the five formulations, the data for a paddle speed of 20 rpm are below 60 rpm, which shows a higher densification for a higher paddle speed as expected. Furthermore, the difference between the intercepts of the two paddle speeds increases with increasing DCPA mass content. The difference reflects the stronger influence of the paddle speed on the apparent density inside the die, and probably inside the feed frame, for excellently flowing powders. It easily enters the die cavity during filling, and might firstly be densified by the high amount of powder provided by the paddles, which overtake the dies (PS3). The good flowability of these formulations allows fast and easy rearrangement of the particles, which can contribute to a denser bulk. Further densification takes place during dosing out (PS4). Even MCC shows a higher axis intercept for a paddle speed of 60 rpm at a fill depth of 10 mm, which might be explained by the higher fill level inside the feed frame at such a low fill depth.UCF is of special interest. For the pure substances MCC and DCPA, the intercepts are in particularly good agreement with the UCFs of the powders. Thus, at a paddle speed of 20 rpm the dies are completely filled at an apparent density equivalent to the bulk density without dosing out. Densification does not occur. In contrast to the results for the pure substances, the blends do not show a good agreement between the axis intercept and the UCF. The higher intercepts represent an apparent density higher than the bulk density of the blends. Thus, due to mixing effects, the blends show a different densification behavior in relation to the bulk density compared to the pure powders MCC and DCPA. A possible explanation can be found by regarding the bulk and tapped densities of the blends , this critical turret speed is lower in comparison to good flowing formulations (DCPA). In addition, the tablet weight variation coefficient is considerably higher and rises with increasing turret speed. An increase in paddle speed shows a degressive rise in the filling yield for all powders presented and allows higher critical turret speeds, still achieving complete filling. The better the flowability, the lower the minimum paddle speed required to achieve die filling at a certain turret speed. Furthermore, higher paddle speeds lead to smaller variation coefficients. For low paddle speeds  a limited powder mass, which entered the die as of a certain turret speed, is observed for DCPA and MCC, independent from the dosing depth.unconsolidated complete die filling. Two mechanisms are identified which lead to denser bulks during filling: the paddle speed and the dosing out, quantified by the overfill ratio. With increasing paddle speed, especially at low turret speeds and a low dosing depth, the powder in front of the paddles and inside the dies can be densified up to the tapped density for good flowing powder (DCPA). Overfill ratio is identified as an independent factor that causes a linear increase in density. The analysis of the slope and axis intercept of the filling yield over the overfill ratio at different paddle speeds displayed the influence of the process parameters on densification, dependent on the material properties. While the overfill ratio is responsible for an increase in the apparent density for compressible powders such as MCC, the paddle speed has a considerable impact on the densification of excellent flowing powders as DCPA and blends with a high DCPA mass content. However, a correlation with measured powder properties as the Compressibility index was not identified. Besides the densification, the filling yield below UCF differs at the same process parameters for different materials. A linear correlation between the filling yield and the mass discharge rate from an orifice was found for low paddle speeds of 5 and 20 rpm.Higher fill depth and therefore higher dosing depth increase the challenge of obtaining complete filling naturally, especially for fairly flowing powders (MCC). Besides the challenge of filling the dies completely, densification of the powder is observed, exceeding the Based on the general correlations identified in these findings, it is necessary to find appropriate process parameters to achieve complete filling without densifying the powder. Therefore, the paddle speed needs to be high for fairly flowing powders, while the overfill ratio should be small if densification is undesired. In contrast, for good flowing powders, the paddle speed should not be considerably higher than needed to fill the dies completely, if densification is to be avoided.In the future, a prediction of the filling yield should be searched for. Therefore, the courses of the filling yield depending on the dynamic process parameters need to be mathematically described and the influence of the material properties needs to be quantified and correlated to measurable properties. The findings presented here deliver a basis for the model development. Moreover, a scale transfer to larger productions presses and different feeding systems is envisaged.


The complex structure of turning aggravates obtaining the desired results in terms of tool wear and surface roughness. The existence of high temperature and pressure make difficult to reach and observe the cutting area. In-direct tool condition, monitoring systems provide tracking the condition of cutting tool via several released or converted energy types, namely, heat, acoustic emission, vibration, cutting forces and motor current. Tool wear inevitably progresses during metal cutting and has a relationship with these energy types. Indirect tool condition monitoring systems use sensors situated around the cutting area to state the wear condition of the cutting tool without intervention to cutting zone. In this study, sensors mostly used in indirect tool condition monitoring systems and their correlations between tool wear are reviewed to summarize the literature survey in this field for the last two decades. The reviews about tool condition monitoring systems in turning are very limited, and relationship between measured variables such as tool wear and vibration require a detailed analysis. In this work, the main aim is to discuss the effect of sensorial data on tool wear by considering previous published papers. As a computer aided electronic and mechanical support system, tool condition monitoring paves the way for machining industry and the future and development of Industry 4.0. As soon as the machining process starts, the contact between tool and workpiece leads to various events for chip removing and generating a fresh surface ,2. The rPrediction of tool life is a serious issue because of the non-linear and dynamic structure of cutting operations . The comTool condition monitoring system (TCMS) provides online monitoring of cutting operation bringing several advantages such as prediction of tool life, preventing catastrophic failures and increasing the productivity and component quality . CuttingWith the increasing prospects from manufacturers such as precise and punctual delivery which is basically associated with determining the optimum machining environment, several TCM approaches supported by different methods such as deep learning have been proposed . In ordeThe main aim of this study is to summarize the indirect TCMS in detail. The subdivisions of these systems, past studies about TCMS in turning and the relationship of different sensor signals with FW will be investigated. These systems play a fundamental role for Industry 4.0 and heads for cost optimized manufacturing. An increasing trend named hybrid approaches motivates researchers to combine different methods for robust design and accurate evaluation of results ,15,16. TIn this study, TCMS and its subsection, indirect TCMS, are summarized, supported with the published literature covering their structure and main approaches first. Then, sensors used in indirect TCMS such as cutting forces, AE, vibration, temperature, current, sound and image processing along with FW and SR are outlined with their advantages and disadvantages. Data acquisition and signal processing methods are evaluated considering decision-making approaches such as artificial neural networks, fuzzy logic, hidden Markov model, support vector machine and ANFIS. Lastly, critical analysis and trends are outlined to demonstrate the current developments in this field in the perspective of the authors.During more than 40 years of the studies about TCMS, the main focus has remained the same in terms of researchers and manufacturers: to recognize the tool state with several detection systems based on sensors and signal features. Since a single sensor had no capability to detect all or majority of the changes in an operation, multiple sensors needed to be applied in the past. The other side of this issue covers the software part for better understanding of the machining. In the first efforts in this field, Dornfeld and Pan  integratCost optimization and productivity became the main purpose in industry ,26. BreaTCMS are examined in two different categories according to the approach of evaluation of TW in machine tools . Direct Monitoring of tool condition is a constraining and unstable process in machining operations . TW is bAt the beginning of the machining, the cutting tool is sharp . With thIt is suitable to measure the three components of cutting forces during turning operation since each of them can be related to different kinds of TW. Different types and mechanisms of TW can progress on flank face or rake face depend on the load factors . In addiKuntoğlu and Sağlam  performeIn references ,44,45,46Advantages and disadvantages: Dynamometer is a favorable sensor for this purpose due to its sensitivity and high reliability on measuring cutting forces. Dynamometer based CF measurement seems very popular and proper for reliable applications. Since the sensor is situated under the cutting zone, even small load changes can be detected. Although having serious investment cost, dynamometer was the most preferred sensor in the last 20 years in indirect TCMS. Dynamometer is the first choice for researches in terms of using sensor-based systems in turning which exhibits the reliability of this sensor in developing industry. On the other hand, the integration of the sensor is a challenging issue on occasion since its connection needs to be arranged considering the carriage and tool holder mechanism. In the scope of this study, FW related dynamometer usage is about 19.6% of all the presented papers in the last 20 years. The preference rate is high compared with the other indirect sensors which indicate the success of this sensor. For the future prospects, dynamometer integrated to machine tools initially is needed considering the importance of this sensor mentioned before.Acoustic means the science of sound including the vibration and noise which researches the propagation of their waves in solid, liquid or gas mediums. However, AE states the radiation of strain waves in a material subjected to an external load. This exposure leads to deformation of material in different levels such as degradation, breakage or wear. In other words, AE can be defined as the energy release that takes place in the material in micro scale which is deserted from other types of energies for example vibration, force and sound . In machThe prominent motive of using the AE method is its capability of the sense the oncoming events and provides opportunity to take precautions for unexpected developments . A similIn addition to providing information about different components such as cutting tool, workpiece and produced chip, easy implementation of the AE sensor brings esteemed advantage . Since tConsidering its benefits, wide range of usage of the AE sensors is an expected result with the reflection capability of the healthiness of the cutting tool. Kuntoğlu and Sağlam  comparedReferences ,51,52,53Advantages and disadvantages: The characterization of AE signals provides information about machining mechanism and ensuing events at the cutting area throughout metal removing. Minor and major changes during the cutting operation can be precisely sensed via AE sensor when it is positioned in the right way. This brings a clear advantage to distinguish the events as normal ones maintain the cutting and abnormal ones endanger the health of cutting. According to utilization, the sensing scale of AE sensor should be clarified. In a very large scale, some data losses lead to late detection or missing which can end up with tool failure or substantial damages. Especially for the newly developed materials in industry, unknown plastic deformation mechanism and possible tool breakage scenarios push the researchers to use the AE sensor. It is needed to observe the fluctuating changes occurring in the material to better understand the behavior of cutting tool and workpiece during cutting operation. AE sensors have been preferred in the last 20 years covering the FW detection with the rate of 16.3%. Considering the increasing effect of the richness of the information on detection of tool wear and tool breakage, it is reasonable to select this sensor in wide scale. It was observed on the previous study from author . Th. Th99]. B. Mechanical, chemical, diffusive seem to be the major load factors affecting the FW [FW is the type of wear caused by the friction that occurs between the insert clearance angle of the cutting tool and the new surface of the part corresponding to this angle. The width of the FW is indicated by Vg the FW ,119.FW develops on the flank face of the cutting tool as a result of several parameters. Too high cutting speed, plastic deformation resultant of too high cutting temperatures and edge chipping caused by excessive load on the cutting tool are the main factors on FW .In the studies made on AISI 4340 ,121, AISIn turning, it is important that the tool continues cutting operation with high performance for optimum tool life . AlthougKuntoğlu and Sağlam  performeAdvantages and disadvantages: Since the tool wear inevitably develops on the cutting insert, it should be kept under control to understand the underlying mechanism for avoiding excessive levels. In this direction, one of the main advantages of it is that online monitoring of tool wear is feasible with indirect sensors without stopping the operation. Due to FW increases on the main cutting edge and proper for quantifying with standards, its detection offers vital information about the remaining useful life of the cutting tool. However, the sophistication because of the numerous cutting parameters and variables aggravates accurate estimation of tool wear on occasion. In order to validate the wear progression rate, this is necessary, which leads to high investment cost for reliable and sustainable manufacturing.1.Waviness (Irregularities with measurement ranges greater than surface roughness sampling distance);2.Defects ;3.SR .In engineering applications, the desired surface shapes in part are expressed as the nominal surface. The surface texture consists in repeated deviations from the nominal surface of the part, and these deviations are the following:These are expressed by their properties. The average of vertical deviations at a certain distance of a surface that has undergone a certain treatment is called SR. Today, the method of average SR is frequently used as a method of determining SR. This method uses an arithmetic mean based on the absolute value of deviations, and this method can be expressed by Formula (1) .(1)Ra=∫aR = average arithmetic SR, mL = distance measured, y = deviation from nominal surface. Although there are many methods to measure SR values, needle point devices, and devices using optical methods  are among the most used methods. Besides, recently, there were techniques in which 3D graphics of the surface were created to detect SR [In this formula, it is defined as etect SR .Considering the technological developments in recent years, it can be seen that excellence was aimed in terms of product quality. In The parameters affecting the SR can be evaluated in two main groups as dependent and independent variables. While parameters such as AE, vibration, temperature, CFs and TW are dependent variables; feed rate, depth of cut, part material and insert are shown as the parameters that affect the SR independently ,146,147.In recent years, SR estimation and optimization of these values have become very important for the industry. In steels, AISI 4140 , ADI (grKuntoglu et al.  performeImage processing is a pattern recognition process that works with a strategy based on measurement of image textures in a variety of application areas such as statistical data analysis, machine learning and signal processing . These sMannan et al.  used imaAccording to papers ,79,80,81Advantages and disadvantages: Different from the mentioned sensor systems, image processing is applied after machining operation is completed. This situation brings a disadvantage since the prevention of tool breakage and excessive tool wear becomes difficult and almost impossible. However, when the machining stopped for different reasons, such as measuring of surface roughness, it is possible to employ pattern-recognition-based applications. This approach provides additional information about tool and can be beneficial for confirmation of the collected sensor data. It is noteworthy that well-structured software can predict the situation of the tool within high success rates, which improves the quality of machining by far. According to published papers in the field of monitoring of turning operation for FW, it was found that 9.8% of the studies preferred image processing techniques for that purpose. This can be explained by the incapability of these systems to intervene in the machining processes.After the experiments under specified cutting conditions, gathered data needs to be evaluated with proper methods, which give accurate information to operator or machine learning algorithm for final decision. In the signal processing phase, the researcher needs information about the analysis method ideally reflecting the signal features. Very popular signal processing methods to evaluate tool condition are outlined in this topic . SeemingGathered data from sensors through data acquisition systems was handled for final decision about the quality characteristic . This prOne of the most popular decision-making methods is artificial neural network model inspired by the working mechanism of the human brain. The model contains three or more layers, each one set with number of neurons. The first and last layers indicate the input/s and output/s, respectively, and the neurons in these layers should be connected to each neuron in the hidden layers. One crucial point during modeling of neural network is the necessity to have experience in and knowledge about determining the number of hidden layers and neurons. However, depending on the inputs and outputs, the relationship between parameters, number of hidden layers and their neurons needs to be revised and constructed. The connection between each neuron in entire layers is provided with weights which require training for the best solution. After the training procedure, it is expected to obtain the value of the response parameter from the output layer. There are several factors affecting the performance of the neural network structure such as training time, transfer function, weights, learning function . In addiIn the particular example of this paper, FW prediction via artificial neural network in turning operations using different types of materials has been an attractive issue in the past. In references ,84,85,86Fuzzy logic uses membership functions to link the input and output parameters via predetermined rule list. It is actually a reasoning-based methodology provides to estimate the desired parameter from 0 to 1 possibility. Human observation and the way of thinking is the example for development of the fuzzy logic approach. Fuzzification, rule editor and defuzzification processes are respectively applied to input data values. At first, the range of membership functions are defined with the training of input values; then, using rules, inputs and outputs are linked to each other, and lastly, fuzzy terms are converted to numerical values again with defuzzification. There are two basic fuzzy types, as Mamdani and Sugeno, in the modeling interface of fuzzy logic. In the prediction phase, methods should be identified, namely, and, or, implication, aggregation and defuzzification. The membership functions of inputs and outputs, type of fuzzy and decision methods are demonstrated in Hidden Markov model is based on an observation strategy for the modeled system, which proposes to learn it via Markov process. Being another process, behavior is assumed as dependent and should be handled separately. Markov process is evaluated as a hidden or unobservable condition using the actual data in the system, which further ensures the validity of the result . The usaSupport vector machine is a supervised classification method in machine learning applications starting with the separable data at first, then modifying it to solve the problems having non-separable data . As it iAdaptive network based fuzzy inference system is a combined neural network and fuzzy system which is based on extraction of fuzzy rules for every layer of neural network model. The structure of the adaptive network based fuzzy inference system is indicated in Necessity: Basically, online monitoring of tool condition seems highly necessary to prevent unexpected developments, better component quality and optimized cutting conditions. A certain investment on TCMS provides more efficient and low-cost manufacturing in industry.Purpose: Generally, any improvement in the field of optimization can be one of the purposes of TCMS such as surface quality, dimensional accuracy, tool life, consumed power and energy, manufacturing time, manufacturing costs, idle time and waste material. Moreover, optimum cutting conditions can be obtained via TCMS, which will fulfill the aforementioned purposes within a particular quality.Primary advantages: Online monitoring of tool condition provides avenues to interfere the operation instantly with qualified equipment. Artificial-intelligence-based monitoring acts as a decision making mechanism rather than operator and makes deductions with high reliability.Additional advantages: Beyond monitoring machining conditions, these systems provide significant data source and optimized parameters for further usage. Besides, healthier turning conditions for operators can be obtained by preventing accidents. If TCMS is supported with supplementary device such as withdrawal mechanism; the intervention can be performed without operator control.Coverage and context: Especially in machining operations, for turning, drilling, milling, etc., TCMS proved that more accurate and sensitive manufacturing can be obtained. However, proper sensor systems can be integrated to any manufacturing technology and successfully applied.Drawback and deficiency: There is a need for investment cost to meet sensor systems, data acquisition equipment and software for data processing and recording. Multiple sensors can detect the system errors more accurately and predict tool condition with more sensitivity. It is an important issue to determine the number of sensors because of bringing additional financial worries.Recommendation: A universal approach should be developed instead of a certain pair of tool and workpiece investigation for each study. That is why the relationship between process parameters and TW should be analyzed and stated in detail. Description of sensor fusion must be clarified and generalized for robust, inexpensive and intelligent monitoring systems.Previous research work: In the far past of turning operations, a series of cutting tool materials have been applied to newly developed workpiece materials to achieve better machinability. With each of work material produced, it was intended to solve the several industrial and social problems, however innovations introduced new issues. In order to overcome these problems of each period, technological approaches presented from manufacturers and researchers such as new tool geometry, developed machine tools, different cooling technologies, the latest tool materials etc. As mentioned before, each of these initiatives accompanied mysteries and questions. TCMS evolved in time for different types of problems, unexpected failures, industrial accidents, to control the new technology and came to modern day. Even though it seems with the name “tool condition monitoring”, the system monitors the machine tool and workpiece. The basic structure of this system is available to integrate modern hardware and software components. Therefore, their existence provided a reliable manufacturing in the past and of course, will be the most important assistance in the future.Turning is a widespread machining operation that can efficiently remove chips from a rotating and cylindrical workpiece. Cutting tools are the main components of an entire production chain dealing with the workpiece which is considered as the ultimate aim of manufacturing. Turning tools are employed to change with new ones before reaching wear limit for healthier and low-cost operation. Tool breakage is a devastating event causing diverse damages such as machine downtime, workpiece deterioration and increased total costs. Unexpected tool breakage and usage of a cutting tool in lifetime requires TCMS that can diagnose the tool condition with sensor systems or pattern recognition approaches. Indirect TCMS are more suitable for industrial applications because of their applicability and sustainability and for being economical. Besides, the papers which have motivation to correlate the sensor signals with tool FW using indirect TCMS are included in this review. A general outline was performed on indirect TCMS for turning operations in this study for the last two decades. Advanced monitoring systems and their integration to manufacturing systems serve as a supportive component for production of complex parts. These systems enable detection of errors in cutting tools and workpieces for higher accuracy. Moreover, it is possible to set communications between sensors and machine tools to make decision for the health of the machining. Software based solutions can be obtained in this manner, which is a better approach for the management and supply chain in a production platform. In the future, it would be also possible to integrate different combination of advanced cutting tools and new generation materials. The experience on machining to date is a guide for this purpose, but there is a requirement for advanced artificial intelligence systems and their successful integration to manufacturing processes. The selection of appropriate signal processing and evaluation methods after choice and accomplished integration of sensor systems is noteworthy. There is need for complete and multi-disciplinary information on robust and high accuracy monitoring systems. TCMS based systems became reliable auxiliary especially in turning operations enhancing the quality of the workpiece, tool life and productivity. Besides, further applications on monitoring of cutting tool can be improved to adaptive control systems for online decision making. The following implications can be derived according to authors:Mentioned topics for sensors and signal processing methods are handled and evaluated one by one in this paper. It should be noted that there is necessity to compose these hardware and software sources to follow future trends. Not only for a sensor and an artificial intelligence method but also using more than one sensor to obtain sensor fusion integrating hybrid decision making methods for a robust process. For that purpose, Industry 4.0 leads in industry with increasing expectations because of its extensive content which covers the intelligent manufacturing, smart manufacturing, sustainable manufacturing and digital manufacturing. Gathering these methods is just the beginning of the period. With newly discovered materials and developed models, previously proposed methods need updating especially for avoiding excessive costs, idle time, material losses and hard to recover mistakes. To date, all proposed methods addressed the technology in some way however with increasing interaction between humans and machines should direct it to develop faster and efficient. In the perspective of machining technologies, TCMS exist in a significant position providing reliable information about complex machining operations.The prominent sensors have been considered as dynamometer, AE, temperature and accelerometer with their success in detection and preferability in the field of TCMS in turning. Almost all of these sensors are expensive and increase initial investment costs. However, advances and complications in machining technologies make these sensors essential, applicable, tenable and sustainable for online monitoring. Clearly, their quick response time and easy to implement structure is attractive to solve the sophistication while turning. For improved diagnosis and prognostics, the accurate implementation of decision-making methods for different types of sensors is notable. This situation generates a problem that there is need researchers represent different disciplines for more profound analysis during preprocess and post process. An important issue is fast convergence of the parameters for optimal values which can be possible using emerging data analysis methods. The integration of different types of data for an ultimate decision about the operation should be performed. Another challenging issue is collecting data together and analysis them which require comprehensive information that entail the utilization of data communication for health monitoring. In order to practice the prognostic health management with intelligent systems, the emerging technologies in the field namely edge computing, machine learning integrated embedded devices should be used. These systems monitor the operation with advanced software components for sustainability of the production while managing cost and safety. High technology supported manufacturing systems ensures the diagnosis of major errors affecting the dimensions of the workpiece and reducing remaining useful lifetime of the cutting tool. Generally, condition-based maintenance systems preserve the available situation which is predetermined by operator accepted that as the optimal condition. Eventually, for the purpose of the Industry 4.0, a holistic approach is required to avoid a variety of defects and breakdowns during the turning operation.Artificial neural networks and ANFIS applications have been utilized satisfactorily in turning operations for FW as it can be clearly seen. These methods were first among the others which demonstrated the success of neural-networks-based prediction and monitoring. With this survey, it is intended to show the primary applications on sensors and decision-making technologies, their advantages and drawbacks. It is suggested that a specific TCMS equipped with correct sensors, signal processing method and classification is the most developed one for a specific work material. That drives the researchers to investigate each sensor feature and signal processing method in detail.The cross interaction between cutting parameters, in addition to the effect of TW mechanisms and TW types, makes cutting operation complex. Considering turning, single cutter is exposed to high mechanical, chemical and thermal loads which lead to different wear developments. FW is accepted as the main tool life criteria since it shows progress on the flank face and weakens the main cutting edge. Therefore, it is required to analyze in detail the FW especially with sensor systems to investigate their correlation. In this way, online tracking and detection of the condition of wear can be determined and further prevention of failure can be possible.The estimation of FW is a difficult task due to the time variant and non-linear structure of machining processes. This challenge pushes the researchers to observe the momentary alterations and protect the cutting tool from harsh conditions. Having a long history, TCMS served as an information source with developing systems. A subsection of TCMS is indirect systems, which are easy to implement and which provide effective solutions, when the previous papers are considered.As each innovation brings some inconveniences, the drawbacks are due to lack of knowledge, supplementary payment and possibility of inefficiency. Indirect TCMS presents valuable contributions such as capability of using cutting tools in their remaining useful life. This process can be managed by optimizing the other operation variables. Eventually, this technology offers a facility that brings multiple optimization of cutting variables along with the ultimate aim of the process parameters.The summarized methods belonging to signal processing and sensor systems prove the significance of different applications in order to solve various machinability problems related with TW. Considering the literature, a problem may be solved with a variety of techniques and with one way in some situations. That drives the researchers to find the correlations between variables and FW.As outlined, each sensor has some advantages and disadvantages; however, most of them develop the monitoring system enduring the tough conditions of machining for a long time. Thus, proper selection, integration and usage of a sensor or a group of sensors make the high costs of this investment tolerable. Manufacturing technologies extend their facilities with labor, economy, and engineering information in order to reach the goal of Industry 4.0. This committed literature review shows the importance of indirect TCMS for reaching the objective of Industry 4.0.Despite there being important initiatives to evaluate TW, CFs, vibration, AE and SR, analysis, modeling and optimization were performed individually in some studies. On the other hand, a number of papers published in the field endeavored to estimate process parameters accurately. To date, important work has been carried out to correlate TW and sensorial data in turning. Thus, a critical review should be performed for TCMS to explain the relationship between sensorial data and quality characteristics, for example, TW. The following conclusions were drawn from this exhaustive literature review:This paper focused on summarizing the relationship between indirect TCMS sensors and FW. Published papers in the last two decades in this area were outlined, data acquisition, signal processing and decision making methods were also investigated. The research can be carried out for milling and drilling operations and other types of TW.


Risk factors such as smoking and sugar intake threaten the health of human being at an individual national level as well as at a global level. The globalization affect health indirectly through macro and micro-level factors. This study aimed to identify the global trend of dental caries according to countries national income level, and to examine the role of globalization, health services, obesity, and sugar consumption on dental caries. Data for 160 countries were collected for the time period of the 1990s to 2010s. The final sample included 46 countries with complete data (21 high income countries (HIC) and 25 middle and low income countries (MLIC)). The main dependent variable was the mean decayed, missing, and filled teeth (DMFT) index of 12-year-olds as an indicator of dental caries. Globalization was a main independent variable which was measured by economic growth, urbanization and economic freedom. Other independent variables were health services, obesity and sugar consumption. The data were analyzed first using repeated measures analysis of variance to compare dental caries trends in HIC and MLIC. Then, using multiple linear regression and partial least squares structural equation modeling (PLS-SEM), the relationships between globalization, health services, obesity, sugar consumption, and dental caries were examined. The results of PLS-SEM revealed that globalization was associated with lower DMFT in HIC. The global dental caries trend had a declined pattern, but this pattern has been attenuated in MLIC after the new millennium. There is a need for policy change and regulations on sugar trade especially in MLIC to diminish the adverse consequences of globalization, and to improve population dental health. In the developing countries, a review has reported a global increase in the prevalence of caries. However, other systematic reviews have reported declining and stationary trends in the caries prevalence and severity amongst children.Narrative reviews described a clear decrease of caries prevalence over decades in developed countries. International and macro-level factors promote the development of caries through alterations to the living environment and food choice. A number of comprehensive frameworks have shown the pathways through which international and macro-level factors such as globalization, development, and media programs and advertisement affect health outcomes positively and/or negatively.,8 A modified framework model has been suggested for the way abovementioned international factors relate to caries. Researchers have focused on the pathways that link globalization with general health. These frameworks are ranging from a complex and detailed one, to mid-level complexity and simplified frameworks.,11Many individual risk factors such as poor oral health behavior, lack of knowledge and skills, and unhealthy diet play an important role on developing caries.,12 Therefore, the process of globalization has led to nutritional and lifestyle transitions, resulting diseases, and health services by its impact on national income and the trade.,14 Although it is difficult to directly link nutrition transition with globalization, macro-level factors that lead to changes in diet and nutrition within social systems are linked to globalization such as urbanization, economic growth, free trade liberalization,,15 education.,8Globalization by its definition encompasses greater integration within the world economy through movements of goods and services and also involves the spread of knowledge, science and culture with increase of the global interconnections. This index covers three main dimensions of globalization: economic, social and political. Variable such as international treaties and number of partners in investment treaties are used to measure the political dimension of globalization. Economic freedom involves removing barriers for free trade and foreign investment, including investment in the distribution of food and through spreading out of fast-food chains and multinational food companies. The liberalization of international food trade and foreign direct investment and growth of transnational food corporations, beside global food advertising and promotion, all resulted in increased availability of processed foods, and increase in desirability, diversity, and price of food, which eventually led to nutritional transition. KOFGI measures the economical dimension of globalization using trade and foreign direct investment as a percentage of gross domestic product (GDP). These two variables have a causal relationship with economic growth. Economic growth leads to increase in the trade of goods such as animal products, refined grains and sugar. Hence, rapidly developing countries go through nutrition transition and change on lifestyle at initial stages of economic growth and development. Cultural globalization is one of the measures for the social dimension. The index uses variables such as the number of McDonald's restaurants and IKEA stores in the country to measure cultural globalization. Globally, more people live in urban areas than in rural areas, with 55% of the world's population residing in urban areas in 2018. In 1950, 30% of the world's population was urban, and by 2050, 68% of the world's population is projected to be urban. This global urban growth might lead the McDonald's, IKEA and other brands to spread out and increase in number. Urbanization has led to changes in the living environment and lifestyle, besides the availability of a range of food choices in which all have a direct influence on the quality of diet and energy expenditure. In this study we hypothesize that globalization is related with caries prevalence through the macro-level factors; economic freedom, economic growth and urbanization, as these factors lead to nutritional transitions that ultimately affect caries via biological pathways. The present study aimed to identify the global trend of dental caries according to level of national income, and to examine the role of globalization, health services expenditures, obesity, and sugar consumption on caries prevalence.According to the Swiss Economic Institute, Konjunkturforschungsstelle Globalization Index (KOFGI) is the most profoundly adopted and cited index in the literature.22.1 The final number of countries included in the study with complete data was 46, among them HIC = 21 and MLIC = 25. Figure Data of dental caries, globalization, health service and health related factors for a total number of 160 countries were collected for the time period of 1990s to 2010s. Therefore, the years 1991, 2000 and 2012 were selected as representative years with an average of 10-year interval. The year 1991 was a representative of the late 1980s to the mid-1990s; the year 2000 denoted mid-1990s to mid-2000s, while the year 2012 represented the late 2000s and early 2010s, so the data for the adjacent year was used in case of the data was not available for the exact selected year. After that, the countries were divided according to their level of income based on World Bank classification for the year 2010 into two groups, the first group included High Income Countries (HIC) = 47, while the second group included Middle and Low Income Countries (MLIC) = 113.; Organization for Economic Cooperation and Development for countries with missing data of DMFT; The World Bank data of GDP per capita based on purchasing power parity, health expenditure per capita , public health expenditure as a percentage of GDP, and urban population % of total population; Institute for Health Metrics and Evaluation-University of Washington data of obesity, mean value for the age group 10 to 14 years; and the Heritage Foundation data of economic freedom. The approval of institutional review board was not necessary because all data used in this study were publicly open data.The data were obtained from the online data bases of the following, Malmö University data of DMFT and sugar consumption2.2 Globalization; the main independent variable, was measured by GDP per capita as an indicator for economic growth, urban population as an indicator for urbanization, and economic freedom. Health service and Health related Factors (HRF) were both mediator factors and served as dependent and independent variables. Health service was measured by health expenditure per capita and public health expenditure (% of GDP), while HRF was measured by sugar consumption and obesity. Eventually, time-variable is represented by the years 1991, 2000, and 2012.The dependent variable was dental caries. It was represented by DMFT index values for 12-year-olds, which describe the caries experience in an individual. Obesity as well has been associated with caries and both share common risk factors.Health service was represented by public health expenditure as a percentage of GDP that reflects government spending on health sector and also represented by health expenditure per capita that shows the peoples’ share on the spending on health services which in turn affects their use of these services and their general and dental health. Sugar consumption and obesity share common risk factors, and both have been associated with caries. Increase sugar consumption is one of the outcomes of globalization and there is evidence supports the relationship between the amount of sugars consumed and caries development.2.3P < .05), therefore the Huynh-Feldt corrected tests are reported. Next, using multiple linear regression, the variables were adjusted in a serial fashion. The first model included sugar consumption and time. Both variables were chosen as the basic model because the association between sugar consumption and caries is already proved with evidence and the purpose was to see how other variables affect this association. Model 2 comprised of model 1 and obesity. In model 3, health service indicators were added to model 2. Lastly, in model 4, globalization indicators were added to the other variables in model 3. Multiple linear was carried out using SPSS.23.0  and the critical level of statistical significance was set at P < .05.A one-way repeated measure analysis of variance (ANOVA) was first applied to compare the mean DMFT values of HIC and MLIC, and to compare these values within each group at the selected time periods. Mauchly's Test of Sphericity indicated that the assumption of sphericity had been violated  was conducted. PLS-SEM is a powerful analytical method because it works competently with small sample size, can be applied to any data scale, and no distributional assumptions are needed. Convergent validity was assured by the assessment of the outer loadings. All outer loadings were significant (P < .05) except HRF indicators in HIC model, and all exceeded the minimum threshold of 0.4 for exploratory research as suggested by the study of Hulland. The average variances extracted (AVE) of the constructs in the proposed models were all more than adequate; over 0.5, except for HRF in the HIC model. For the discriminant validity assessment, all indicators had the highest loading in their corresponding construct in the model and the square roots of AVEs of each construct were greater than the correlation of the specific construct with any of the other constructs in the model except for globalization as it was highest with HRF in the MLIC model.The measurement models assessment for both groups; HIC and MLIC, are shown in Table f2 effect size of each path for HIC model reveals that the paths from globalization to dental caries and health service had large effect size. On the other hand; the f2 effect size of each path for MLIC model shows that the paths from globalization to health service and HRF had large effect size. Whereas the path from time to caries had medium effect size.Hypothesis testing was done by the assessment of structural models. A bootstrapping technique with 500 adjusted samples was applied to check the validity of the structural relationships among latent variables and to estimate the significance of the path coefficient. The exploratory path models that were tested in this study demonstrated the hypothesized relationships between the independent latent variables and caries. The results of the preliminary collinearity check showed that all variance inflation factors (VIFs) below 5.0. The R2 values (adjusted R2) revealed that in HIC model, the independent latent variables explained 52.6% of the variance in dental caries, which indicative of a very strong explanatory power. On the other hand, MLIC model explained 23.8% of the variance in caries, which revealed a moderate explanatory power. Furthermore, both models have acceptable predicative relevance with over zero Q2 value. SmartPLS version 3.0 statistical package is used for the assessment of data analysis.The explanatory power with 3F = 1.95, P = .152). However, there was a significant difference between groups in the mean DMFT index only in the year 2012 (P < .01). The mean DMFT index was always higher in MLIC than HIC at each time period. Moreover, the mean difference was significant for all within group comparisons (P < .05), except for the years 2000 and 2012 in MLIC.The trend of caries showing a continuous decrease in DMFT in HIC, while in MLIC, there is a slight decrease in the DMFT after the new millennium comparing to a more former strident decline Fig. . The resThe results of the multiple linear regression for both groups of countries; HIC and MLIC, are shown in Table P < .001) in HIC, meaning that globalization has an effect on caries decreasing trend when countries become more globalized. Similar to the results of the multiple linear regression, time had a strong negative and significant correlation with dental heath in HIC and MLIC   respectively. Globalization had a strong positive and significant association with health service  in HIC; implying that countries are more likely to provide a better health service as they become more globalized. In MLIC, globalization had a very strong positive and significant correlation with both health service and HRF   respectively, denoting that a gain provision of health service may have improved as countries become more globalized. Additionally, HRF in terms of sugar consumption and obesity increase with globalization.Turning to the results of PLS-SEM, Figure 4,34 However, the declined pattern of caries trend has been attenuated in MLIC after the new millennium indicating that an event has led to this change. Then, this study explored the time effect of globalization, health service and HRF on caries as the hypothesized explanation for the change of caries trend in MLIC.This study presented that caries trend for HIC and MLIC showed continuing declination, and this go in line with previous studies.,36 The results also showed that individual globalization indicators  had no dramatic role on caries trend. The linear regression cannot show the role of individual globalization indicators on the change of population dental health. This is because it cannot account for the complicated relationships among different variables, as it shows the individual effect of these variables not a combined one. Since then, PLS-SEM was used as it offers a great potential to test relationships as a comprehensive means.The results of the multiple linear regression showed that health service  had a greater impact on the association between sugar consumption and caries in HIC than MLIC. This difference could be referred to the higher expenditures for health service, and that a high percentage of these expenditures being directed towards dental health in HIC more than MLIC. These expenditures are invested in treatment and preventive oral care in HIC and whereas in MLIC are mostly used for emergency oral care and pain relief. alongside the low household income, which results in lower use of health services.The results of PLS-SEM showed that the comprehensive variable “globalization” constructed by economic freedom, GDP per capita, and urban population had a great positive association with caries reduction in HIC; however, it had a weak influence in MLIC. This is might be due to the availability and affordability of fluoridated toothpaste and preventive products in HIC, which make them widely used. Beside the high GDP for these countries, which increases the household income that leads to better use of these products and health services. However, this is not the case in MLIC in which these products are not commonly used,,39Globalization has led to a high increase of health expenditure in both groups of countries especially MLIC as a result of economic growth and the increase of GDP. In relation with HRF, globalization had a very strong influence on the increase of the rate of sugar consumption and obesity in MLIC. As economic freedom and policies of trade liberalization lead to raise the availability of sugar and processed food with low nutritional value, which associated with increased rates of obesity and other non-communicable diseases. The PLS-SEM result of the relation between health service and caries in HIC was different from those of the multiple linear regression. Further research on the actual relation between health service and caries is needed. On the other hand, health service had a positive association with caries in MLIC. This might be due to the share of dental health expenditure from the total health expenditure is low in MLIC and mostly used for emergency oral care and pain relief. While in HIC the dental health expenditure is higher than in MLIC, and these expenditures are invested in treatment and preventive oral care.,36 HRF had contrasting associations with caries as they had negative association in HIC but positive one in MLIC. This could be due to inadequate exposure to fluorides and absence or limited public health measures with the increase of sugar consumption and processed food in MLIC.The results of PLS-SEM also showed that the association between health service and caries prevalence in HIC was negative but not significant. This might be due to that the DMFT scores were represent the F component of the index (demonstrates treated caries) which is an indication of greater access to dental services in developed countries. Another possible explanation is that dental caries is higher among the lower socio-economic class who has inadequate access to dental services in HIC. mainly on caries prevalence. Additionally, the data were often collected at different time points, which may have introduced some degree of variation in the measurement. Second, due to the repeated cross-sectional design study design, only limited convincing conclusions could be drawn from this study. Third, although this study highlights important associations, it does not demonstrate causality. Finally, globalization may have a role on dental health through oral health behavior, oral health programs and education, but we cannot test this role due to lack of data, so that could be a subject for a future research. In case of PLS-SEM, all items were maintained in the models and that is because of: (1) this is an exploratory research, (2) used for comparison propose between two groups and (3) that the data used were secondary data. Our study does, however, have the following advantages. It is the first study to explore the role of globalization on the global caries trend in a comparison between HIC and MLIC using different statistical methods. Besides that, we used all the available online data of the selected variables.Our study has several inevitable limitations that should be considered: first, the objectives of this study were assessed on an ecological level. Therefore, the study is subjective to some methodological limitations mainly “ecological fallacy”. Besides that, the difficulties in ensuring the reliability and validity of the measures, particularly given the range of different groups involved in the data collection,In conclusion, caries trend in HIC and MLIC has shown a declination pattern over time but this pattern has been attenuated after the new millennium in MLIC. From our findings it can be implied that the globalization was associated with lower DMFT in HIC, and had a strong association with increase of the health expenditure in both groups of countries especially MLIC. Moreover, globalization has been associated with increase of sugar consumption and obesity in MLIC. Therefore, based on these findings, this study suggests that regulations and policy change related to the trade of sugar has to be implemented, particularly in MLIC as they considered the favorite market for big food companies. Future research is to be directed to examine the role of oral health behavior, measures and educational programs, and type of health and political systems on the relation between globalization and dental health.Jihyun Lee and Changyup Kim for their support in implementing this research.We are grateful to Professor Dong-Hun Han designed the study. Bakr Salem Alsuraim collected the data, performed the analysis, and drafted the manuscript. All authors read the manuscript and are responsible for it.


The diagnosis of parkinsonism is established by the presence of tremor, stiffness and bradykinesia alongside with neurological examination, requiring the exclusion of secondary causes such as stroke, hydrocephalus and infectious diseases. Included in this last category, neurocysticercosis is a disease caused by Taenia solium, with a variable clinical presentation that can include epileptic seizures, hydrocephalus and rarely parkinsonism. In the reported case, the syndrome is a consequence of lesions in the nigrostriatal dopaminergic pathway caused by the implant and mass effect of the cysticercus. The authors report a case of parkinsonism in a 59-year-old woman with a previous history of neurocysticercosis who presented with hydrocephalus on magnetic resonance imaging exam. The patient was treated with pharmacological therapy and ventriculoperitoneal shunt, progressing with amelioration of the symptoms presented. Parkinsonism is characterized by the triad of tremor, stiffness and bradykinesia . MedicalCysticercosis is a disease caused by Taenia solium larva and has two syndromic presentations: extraneural and NC. The latter, in endemic countries, is considered the main cause of seizures in adults . Other pA 59-year-old woman was admitted with progressive symptoms of urinary incontinence, amnesia for recent events, failure to recognize family members and difficulty walking since four months ago. She had a wide-based gait and stiffness predominating in the lower limbs, which later evolved to incapacity to walk and bradykinesia. The patient was diagnosed with NC 20 years ago and epilepsy approximately 15 years ago, treated with phenobarbital. She sought assistance from a neurologist, who performed a lumbar puncture in order to assess the persistence of symptoms after removing excess of cerebrospinal fluid (CSF). The lumbar puncture showed CSF of normal characteristics. The patient showed no improvement in symptoms after the procedure and was referred to the hospital for diagnostic investigation. Admission laboratory tests showed no pathological changes. Axial , having excluded other possible similar pathologies Figure  7]..7].As for the clinical case presented in this article, the treatment for parkinsonian syndrome presented by the patient is mainly the treatment of the underlying etiology , obtaining improvement with the insertion of a VPS. In cases of active cystic lesions, a recent study showed that the combined therapy of praziquantel 50 mg/kg/day and albendazole 15 mg/kg/day for 10 days was more effective than the use of a single drug, without causing greater side effects. At the beginning of treatment, corticosteroids are often used for a few days associated with cysticide therapy to minimize cerebral edema caused by the death of cysticerci. Dexamethasone and prednisone are the most frequently used medications .The process of resolving acute infection can lead to the formation of granulomas, which can remain to cause the symptoms of the disease in the patient during this process. It is possible that calcified residues remain in the nervous system, which can generate clinical manifestations for a prolonged period of time. Therefore, the use of medications directed to these symptoms may be necessary. Due to the diversity of possible clinical manifestations of the disease, the treatment of NC is a very comprehensive topic, which can encompass several other specific therapeutic strategies, such as VPS and the use of levodopa .NC is a disease that presents itself clinically in several ways, one of which is parkinsonism. Although rare, parkinsonism secondary to NC can cause numerous losses to the patient's life. Therefore, it is extremely relevant that the medical community knows how to recognize this condition, so that it is possible to establish an appropriate treatment for the patient and improve the individual's quality of life. However, it should be emphasized that additional investigation on the subject is needed in order to establish diagnoses and treatments with greater security.


Autism Spectrum Disorder (ASD) is a neuro-developmental disorder that affects communication and behavior with a prevalence of approximately 1% worldwide. Health outcomes of interventions for ASD are largely Participant Reported Outcomes (PROs). Specific guidelines can help support the best care for people with ASD to optimize these health outcomes but they have to adhere to standards for their development to be trustworthy.The goal of this article is to describe the new methodological standards of the Italian National Institute of Health and novel aspects of this guideline development process. This article will serve as a reference standard for future guideline development in the Italian setting.We applied the new standards of the Italian National Institute of Health to the two guidelines on diagnosis and management of children/adolescents and adults with ASD, with a focus on the scoping, panel composition, management of conflict of interest, generation and prioritization of research questions, early stakeholders’ involvement, and PROs. Recommendations are based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision frameworks.Following a public application process, the ISS established two multidisciplinary panels including people with ASD and/or their caregivers. Seventy-nine research questions were identified as potentially relevant for the guideline on children and adolescents with ASD and 31 for the one on adults with ASD. Questions deemed to have the highest priority were selected for inclusion in the guidelines. Other stakeholders valued their early involvement in the process which will largely focus on PROs. The panels then successfully piloted the development of recommendations using the methodological standards and process set by the ISS with a focus on PROs.In this article, we describe the development of practice guidelines that focus on PROs for the diagnosis and management of ASD based on novel methods for question prioritization and stakeholder involvement. The recommendations allow for the adoption or adaptation to international settings. Clinical Practice Guidelines (CPGs) are statements containing recommendations for clinical practice or public health policy. A recommendation describes, for the intended end-user of the guideline, what he or she can or should do in specific situations to achieve the best health outcomes possible, individually or collectively . BesidesFollowing novel national regulations on responsibilities of healthcare professionals , the ItaThe essential behavioral features of ASD are persistent impairment in reciprocal social communication and social interaction and restricted, repetitive patterns of behavior, interests, or activities. These core symptoms are present from early childhood and limit or impair everyday functioning , are ext‘The treatment of children and adolescents with ASD’. [These factors represent challenges for the development of evidence-based guidelines in this field. In 2011, the ISS published the first Italian Guideline on ASD entitled th ASD’.  The publth ASD’. . In 2015th ASD’. . Yet, thThis article introduces the methods and approach to guideline development at the ISS, laying out its innovative methods using the example of evidence-based guidelines for the diagnosis and management of ASD with a focus on PROs.https://cebgrade.mcmaster.ca/guidelinechecklistonline.html). It was intended to meet recommendations for trustworthy guidelines by the National Academy of Medicine (U.S.), formerly known as the Institute of Medicine, the World Health Organization and the GIN [The guideline development process was guided by the ISS methodological manual  and deri the GIN , 17, 18.‘Provisions on prevention, treatment, and rehabilitation of people with autism spectrum disorders, and assistance to families’  intends to ensure the health, the improvement of living conditions and the inclusion in social and working environments of individuals with ASD. The two guidelines described here will be developed in observance of the law 134. Their scope includes the diagnosis and management of ASD and requires describing the perspective, objectives, target population, and target audience.The Italian national law The guideline working group benefits from the contribution of several teams. We describe their roles and responsibilities here.The ISS Steering Committee (SC) leads and oversees the development of the guideline, it defines the groups involved  and supports their productive interaction and it is responsible for the development process including budgeting, the definition of a timeline, and the management of COI. The SC, coordinated by a principal investigator and supported by scientific and technical secretariat, selected two chairs for each guideline: one content expert and one methodological expert. The chairs are included in the SC together with a quality assurance team that ensures the compliance of the development process with the ISS methods and regulations.https://gradepro.org), work closely with the guideline panel in prioritizing the relevant questions and outcomes, prepare background documents for the guideline panel and stakeholders, coordinate teleconferences and online voting processes, review comments.The guideline group or panel is responsible for prioritization of questions for the guideline, participation in group meetings and teleconferences, providing input on evidence and contextual factors, reviewing evidence summaries, making judgments and formulating recommendations in final panel meetings, reviewing and writing of final guideline report and support for dissemination . Two sepThe Evidence Review Team (ERT) searches the literature and produces syntheses of the evidence. Following the GRADE approach, the ERT rates the certainty in the evidence, prepares the GRADE evidence tables and Evidence-to-Decision (EtD) frameworks that the panels use in formulating recommendations.The ISS policy on the management of COI follows the GIN principles for disclosure of interests and management of COI in guidelines  and it iThe working group met for the first time in a two-day meeting held at the ISS headquarter. The following activities took place: the SC outlined the scope of the guideline; guideline developers presented the existing guidelines on ASD; the working group discussed the resources and time available and agreed to produce recommendations on 16 research questions for each of the two ASD identified populations over an 18-month time period. The guideline quality assurance team presented the ISS policy on COI and collected COI disclosure forms from participants. The ERT introduced the GRADE methodology in two presentations. The first presentation served as introduction to the GRADE constructs of certainty in the evidence and strength of recommendations , 22. TheWe implemented a two-step approach that allowed panels to identify and agree on the questions to be addressed in the guidelines using the module in GRADEpro that allows for the generation and prioritization of questions and health outcomes .Guideline developers drafted a list of strategies and interventions addressed in existing CPGs on the diagnosis and management of ASD –31. We dOnce the list of candidate questions was finalized, we asked panels to rate the priority of questions on a 1 to 9 scale. We used surveys electronically generated in GRADEpro  to the groups in separate two-hour teleconferences using the mean rating score as a ranking criterion. We invited the groups to critically appraise the list and to evaluate its harmony. In particular, we asked to verify if any of the top-rated questions for inclusion could not be considered as exhaustively informative to the reader if not paired with another question that was not rated for inclusion. To achieve harmony, we also organized questions in sensible units, consisting of the smallest recommendation sets that would be informative or required for readers to avoid gaps and achieve rapid dissemination . We usedhealth outcome descriptors, to reduce the risk of introducing error that could result when panel members have different understanding of the same outcomes. We then sent GRADEpro surveys asking to add, for each question separately, potentially relevant people-important outcomes that were not yet included in the list drafted by the PRUs  over a four-week period. Example of questions used in the questionnaire are available in Additional file www.osservatorionazionaleautismo.it) where recommendations and the underlying evidence will be available for different user profiles, similar to those of the European Commission Breast Guidelines [Guideline panel members reviewed the comments that were collected electronically using a structured questionnaire (idelines .https://www.webex.com/), to allow off-site participation and visualization of content on the screen of panel members’ devices while discussion it. To pilot the online approach, we used the PanelVoice module of GRADEpro (https://gradepro.org/panel-voice/). Through electronic surveys that are integrated in the EtDs, PanelVoice enables guideline developers to facilitate the decision-making process electronically. The process starts with the collection of panel judgments on the EtD criteria  Fig. .Fig. 5CBetween June and July 2018, the steering committee received 158 applications for the two multidisciplinary and multi-professional panels of independent experts. Twenty-six applicants were not eligible because employed in private healthcare facilities or universities, had undocumented declared professional competences, their professional profile was not requested in the public selection announcement, or they applied after the submission deadline. Among the 138 who met the requirements, the SC selected 16 applicants per panel on the basis of their professional and personal experience, expertise, healthcare setting , and geographical representation. Table The SC reviewed the detailed declarations of interest of all the 158 candidate panelists. None of them was prevented from participating in the panel because of relevant COI, since all the interests declared were considered as manageable through measures such as partial exclusion or public disclosure. Afterwards, the SC evaluated the panelists’ declared and non-declared interests, the latter identified through surveillance of research projects or training activities in which experts are engaged. The SC did not identify any relevant COI that would have prevented guideline panelists from participating in the generation and selection of the research questions addressed.We abstracted interventions and management strategies from previous guidelines into 7 macro-areas to create an initial list: diagnosis and assessment of ASD core-symptoms, diagnosis and assessment of ASD associated features, comorbidities, differential diagnosis, pharmacological interventions, psychosocial interventions, other non-pharmacological interventions. Strategies within the same macro-area were categorized and grouped together by the PRU where applicable. Categorization was based on the target population (e.g. people with ASD versus their caregivers) and on the theory underpinning the interventions. Due to the availability of multiple theoretical frameworks related to non-pharmacological interventions for ASD, the latter categorization presented challenges that we solved through discussion. As for the population of children and adolescents with ASD, the process resulted in a list of 79 questions of which 27 were high-priority, 46 questions important, and 6 questions not important. As for adults, we generated a list of 31 questions of which 21 were high-priority and 10 questions important. For each population, we will develop recommendations to answer 16 research questions whereas all other questions will be mentioned as not prioritized in the guideline. Tables The panel responsible for children and adolescents with ASD rated ASD core-symptoms as critical outcomes for all research questions. Impairments in social interaction and communication, and restricted and repetitive behaviors were considered as distinct core-symptoms of ASD and rated separately. Other critical and important outcomes included quality of life, adaptive functioning skills, and parenting stress. The panel responsible for adults with ASD prioritized outcomes related to quality of life and outcomes such as social inclusion, level of independency from the caregivers, overall functioning and professional competencies. Other important outcomes included core-symptoms, behavioral disturbances, psychotic symptoms and treatments’ side effects. All outcomes were PROs.Of the 129 stakeholders that requested to comment on the list of questions identified for inclusion in the guideline, 115 met the eligibility criteria. We excluded stakeholders for the following reasons: the application process was not completed or the relationship with healthcare industries was not declared. Figure The majority of comments pertained to potentially relevant subgroups and outcomes that were not considered in the prioritized guideline questions. Many stakeholders requested clarification regarding the meaning of “standard of care” which was used to phrase some of the questions. Based on the feedback received, we reviewed the comments and improved the wording of research questions and added new sub-groups, where necessary.The questions identified for piloting the process focused on the impact of polyunsaturated fatty acids on PROs in children and adolescents with ASD. The body of evidence consisted of Randomized Controlled Trials (RCTs) and the overall certainty in the estimated effects was rated as very low owing to serious indirectness and very serious imprecision. Based on the very low certainty in the evidence of effects and uncertainty in other judgments on EtD criteria, the panel made conditional recommendations. Further details on the pilot questions, including the EtD framework with panel judgments, are available in Additional file We have described the methods and processes for guideline development at the ISS using the diagnosis and management of people with ASD as an example. It is the first guideline that follows the new ISS standards and has posed a number of methodological challenges that we addressed using novel guideline development approaches . A challThe heterogenous composition of the panels, which includes health professionals and stakeholders across a broad spectrum, reflects the complexity of the condition being addressed. The management of such large guideline groups, which encompass different professionals and potentially heterogeneous viewpoints, requires particular ability by chairpersons to conduct effective meetings. Given the broad interest in this guideline by many and diverse stakeholder groups, the process requires maximum possible transparency and we tackled this challenge through the use of GRADE EtDs, the early involvement of key stakeholders and press releases. Applying the ISS COI policy revealed the need for a cultural change. In fact, experts are often not aware that having published on the topic of interest or carried out research or professional activities in the field constitute an interest to be declared. This is important not only for disclosure purposes but also for allowing an assessment of potential conflicts and for determining measures to manage them. We provided guidance to experts in this process to enable them to recognize and declare any circumstance in which a secondary interest could interfere with the impartial performance of their duties, functions and tasks.We created a large multidisciplinary panel which include people with ASD and their caregivers and operate under a transparent policy on COI. Our process for prioritization, using a structured and transparent approach, granted equal voices to panel members and focused on PROs. Our process is supported by independent systematic reviews by the ERT which include an assessment of the certainty in the evidence according to the GRADE approach. We used health outcome descriptors to minimize the bias and improve the overall transparency of the process. Using the GRADE EtD framework, criteria and judgments that yield recommendations are transparent and allow targeting to different user profiles . ThroughWe used information technology to streamline the development process and improve efficiency. Indeed, web-based decision-making and communication tools such as of GRADEpro, StarLeaf, and Webex facilitated work logistics and decreased costs associated with in-person meetings while increasing panel members’ involvement. We promoted stakeholders’ involvement from early stages of the process. The ISS SNLG web platform ensured a transparent and participative process in which stakeholders are empowered to provide valuable feedback in several phases of the process.Guideline development requires advanced methodological skills and understanding of evidence. Although panel members are not formally required to know the details of methodology, they must get acquainted with the relevant principles in order to understand the process flow; an ability which demands appropriate training. Human and time resources to develop the syntheses of the evidence that are used to inform the guideline are a very relevant component of the development process but these resources are small compared to the cost of treatment and primary research in this area.We have described the new Italian national guideline development process during its first application in recommendations about the diagnosis and management of ASD. The process seems feasible and acceptable to key stakeholders, including guideline panel members, those synthesizing the evidence and the public. The guideline working group is now developing recommendations that will be disseminated and adopted in Italy. This guideline aims to serve as a reference standard for future guideline development in the Italian setting, and it will allow the adoption or adaptation to various settings, including international jurisdictions.Additional file 1. Interpretation of ratings for research questions and outcomes.Additional file 2. Example of questions included in the questionnaire for stakeholders.Additional file 3. Ratings of research questions for the ISS ASD guidelines.Additional file 4. EtD for the research question used to pilot the process in-person.