Visual cognitive strategies in construction hazard recognition (CHR) signifies prominent value for the development of CHR computer vision techniques and safety training. Nonetheless, most studies are based on either sparse fixations or cross-sectional (accumulative) statistics, which lack consideration of temporality and yielding limited visual pattern information. This research aims to investigate the temporal visual search patterns for CHR and the cognitive strategies they imply. An experimental study was designed to simulate CHR and document participants’ visual behavior. Temporal qualitative comparative analysis (TQCA) was applied to analyze the CHR visual sequences. The results were triangulated based on post-event interviews and show that: (1) In the potential electrical contact hazards, the intersection of the energy-releasing source and wire that reflected their interaction is the cognitively driven visual area that participants tend to prioritize; (2) in the PPE-related hazards, two different visual strategies, i.e., “scene-related” and “norm-guided”, can usually be generalized according to the participants’ visual cognitive logic, corresponding to the bottom-up (experience oriented) and top-down (safety knowledge oriented) cognitive models. This paper extended recognition-by-components (RBC) model and gestalt model as well as providing feasible practical guide for safety trainings and theoretical foundations of computer vision techniques for CHR. Hazard recognition is the first step to prevent accidents . In receHowever, there is still a distance to achieve applying computer vision technology instead of manual inspection for CHR in construction safety management. The hazard recognition performed by humans is a high-level cognitive process ,9. ConstThe nature of the visual search process is an important and typical physiological activity for hazard recognition . PreviouIn summary, the core research questions of this paper are: (1) What are the visual patterns employed by those who successfully identify hazards during their visual search in CHR? (2) Why are such visual patterns employed and what cognitive strategies do they imply?The research objectives are (1) to design and conduct an eye-tracking experiment with real construction scenes pictures as the CHR experimental background to document the participants’ visual sequences during their CHR processes; (2) to introduce TQCA method with the analytical capability for temporality which allows for the inclusion of sequence conditions, and apply it in the visual sequences analysis to identify the visual patterns for CHR; (3) to interpret the visual patterns from both quantitative and qualitative perspectives and explore the visual cognitive strategies of CHR implied by these visual patterns. Further, the practical contributions of the findings to computer vision and safety training for CHR as well as the theoretical contributions to visual cognitive psychology theories are discussed.The rest of the paper is structured as follows: In the last decade, the application of computer vision in construction safety management has become a hot frontier of research , with alSome studies claim that hazards can be identified by specifying some distinguishing features, which is also connoted by feature matching models (FM) . Such stIt has been found that human attention is cognitively driven to differentially allocate between visual areas and shift over time. The lack of such a mechanism means that computers cannot learn and utilize human attentional cues, which is one of the important factors limiting the development of computer vision technology for CHR . On the The completeness model suggests that humans can recognize objects with the same components and structure based on the relationship of the components and the degree to which the relationship “deviates from the prototype” or “average” . In otheMany studies of construction industry have reached a consensus to consider hazard recognition as a visual search task . By docuFirstly, most previous studies have generalized the characteristics and commonalities of visual patterns through descriptive statistics of AOI-based eye movement indicators, such as fixation count ,33, fixaSecondly, the robustness of these AOI-based eye-movement indicators is vulnerable to the impact of the accuracy of AOI definitions. Many studies only labelled AOIs according to expert opinions or the subjective opinions of researchers, which implies a further decrease in these indicators’ reliability and validity of the studies . In ordeFinally, although analyzing visual search patterns based on temporal and spatial sequences in visual scanning paths has been demonstrated to be a valid and appropriate approach and has potential in helping to understand the cognitive process of visual search ,17, currIn fact, one of the main reasons for the above dilemma lies in the lack of appropriate analytical methods that can be applied to visual sequence analysis incorporating temporality. Current research has gradually recognized the importance of temporality for the study of visual patterns and attempted to address this issue. For example, Chong, Liang  used neuAs shown in the study framework in We conducted a hazard recognition experiment in which participants were asked to determine whether the observed pictures of construction scenes were hazardous or safe. All photo material used in the study was collected from construction sites. A total of 60 sets of construction site pictures  were obtained from a pre-developed database that compiled pictures of scenes showing hazardous situations and after rectification (safety). The formal experiment was divided into two parts. Part A: observe 120 pictures that appeared in random order in sequence and complete the judgment according to the paradigm shown in A total of 85 Han Chinese male construction workers with an average age of 42.2 were recruited from construction sites in Beijing, whose ages ranged from 21 to 60 years. All participants participated in industry-specific safety training and were educated in hazard recognition, and the visual process of 69 workers was completely recorded. Further, 14 workers’ data were ultimately excluded to ensure data quality, as their responses were considered unreliable. When judging the scenes shown in the pictures as dangerous or safe, these 14 individuals chose the same response result for more than 90% of the pictures, which could be due to the non-serious response attitude or limited comprehension of the experimental rules. Therefore, the researchers finally selected a sample of 55 male participants for visual behavior analysis. All participants had normal or corrected normal vision with similar work experience in construction projects. This study was approved by the local ethics committee of Tsinghua University (No. 201914). All participants provided written informed consent and received monetary compensation.This proposal is closer to the real conditions of the construction scenario. Since construction workers generally live and work on construction sites for a long time, they have prior observation and comprehension of the construction site without having to be familiar with the environment when performing hazard recognition. However, the 120 pictures selected for this study were from different construction projects in which the participants had never participated. If the participants were directly asked to recognize hazards in the unfamiliar environment, they would have to spend some time familiarizing themselves with the construction scene first after seeing each picture, which might reduce the effectiveness of the visual search sequence obtained from the experiment. As a result, we designed the experiment by utilizing the psychological principles of “working memory” and “priming effect” to give the participants a certain initial impression of the construction site by quickly showing 120 pictures, avoiding the bias caused by spending a long time observing the environment. After that, we selected three pictures with hazards from the 120 pictures for Part B, and let the participants answer under the condition that they were initially familiar with the construction scene. It is worth emphasizing that after the completion of Part A, the participants were not given any information about the correctness of their responses, so the reliability of the responses and experimental data in Part B were not affected by Part A. In addition, this study relied on a large systematic experiment, and the data sources needed in this study were focused on Part B, that is, Part A was not significant for this study. Therefore, for this experiment, the real purpose of Part A was to help the participants become familiar with the construction scenario rather than to use the answers and data from Part A for subsequent analysis or for comparison. In this experiment, the purpose of asking the participants in Part A to answer was to make them concentrate on the construction scenes and memorize them, so as to avoid any possible negligence after being directly told to “just browse”. In summary, the above design can help us to draw conclusions closer to the real construction scene.In Part B, because of the vague impression of the scenes left by the first observation, when participants were asked to observe again, they claimed to perform the hazard recognition task in a more detailed and strategic manner. Examination of the video recordings of visual behavior confirmed the reliability of this statement. In 1974, based on experiments simulating short-term memory impairment, Baddeley and Hitch came up with the concept of working memory as the ability to store information for short periods of time and use the information for cognitive activities such as processing, manipulation, or reasoning when cognitively required . In factOn the basis of “working memory” and “short-term memory”, we can further derive the “priming effect” in psychology. The priming effect refers to a psychological phenomenon in which the perception and processing of a stimulus becomes easier because of the previous influence of the stimulus. Some researchers believe that the priming effect is a manifestation of implicit memory. Accurately speaking, a direct priming effect was involved in this experiment because the stimuli presented before and after were identical. It can be inferred that the working memory formed in Part A had a reinforcing effect on the visual behavior and strategy in Part B, which achieved the purpose of helping the participants to be familiar with the construction scene previously and reduce the bias of the visual search sequence.After the experiment was completed, the researchers interviewed the participants. All participants were asked to review the scenes they judged as hazardous in Part B and describe their observation process as well as the basis of their judgment in detail. For consistency validation, the experimenters recorded and organized the participants’ responses, and then carefully studied the participants’ observation process and visual hotspot diagrams. A total of 55 samples showed high consistency between visual behavior and personal representations.Eye movement data were collected using Tobii Pro Fusion, which recorded at a sampling frequency of 120 Hz. Prior to recording, Tobii Pro Fusion was connected to Tobii Pro Lab software, an integrated software used to design and perform the experiment process and analyze the eye movement data, thus performing calibration to ensure that the camera on the eye-tracking device (Tobii Pro Fusion) accurately tracked the participant’s eyes. The Tobii Pro Lab software has a live viewing function that allows scenes recorded by the Tobii Pro Fusion to be viewed and tagged in real time. Thus, the full course of the participant’s visual trajectory and fixations will be recorded in time and easily found during replay.The raw eye-movement data processing is performed in the Tobii Pro Lab, which allows direct viewing and analysis of the visual behavior data recorded by Tobii Pro Fusion. Finally, for each hazard, the location data of all mapped fixations are output sequentially, and their coordinates are expressed in pixels. The researchers define the locations and ranges of the 3 AOIs based on the descriptions of each hazard in the database, and name them A, B and C. Based on the position of its coordinates in relation to the AOI, it is possible to determine whether the gaze point is located inside the AOI. Based on the coordinates of a fixation in relation to the inclusion of the AOI area in the picture, it can be determined whether it is located inside the AOI. Visual scan paths are generated and represented as a fixed sequence of AOIs. Specifically, the scan path is a string that sequentially shows the AOIs that the observer gazes at in chronological order, i.e., each fixation that makes up the visual sequence is represented by the letter corresponding to the AOI to which it belongs. West et al. suggested two forms of fixation sequences to suit different research focuses . The extIn recent years, there has been an increasing interest in the study of configuration, namely “multidimensional constellations of conceptually distinct characteristics that occur together” . TypicalIn this study, we believe that TQCA is the appropriate method for this study, because (1) TQCA extends the analytical capability for temporality while retaining the advantages of the traditional QCA method, which makes TQCA advantageous in applying to model generalization and integrated synthesis of complex processes involving multiple conditions and time sequences  from both quantitative and qualitative perspectives; (2) based on the TQCA analysis of the participants’ visual searching paths, the visual search configurations with high commonality could be identified, thus helping to address the research question of “What are the visual patterns of construction workers during CHR?”; (3) TQCA allows for the inclusion of sequence conditions in the analysis and preserves the integrity of the sequence conditions in both the analysis process and output results, which helps the researcher to interpret the content of the visual patterns in order to further explore and generalize cognitive strategies.In order to conduct sequences analysis in the TQCA method by existing QCA analysis software and algorithms, this study encoded the observed sequence of any two AOIs as a sequence condition variable  and geneThis study, mainly composed of two parts including necessity and sufficiency analysis that formed the basis of configuration path analysis, used fsQCA3.0 software for TQCA analysis. Necessity means that when the result is produced, a condition always occurs. Sufficiency refers to the explanatory power of a condition in explaining the occurrence of a result . ConsistFor the final result, QCA can produce three types of solutions: complex, parsimonious, and intermediate. This study uses intermediate solutions for a complete representation of the visual pattern in the hazard recognition process. It should be noted that in order to avoid possible interference of the results by chance observation cases caused by individual participant bias and considering the size of the sample size (55 cases), this study set the minimum acceptable frequency cutoff threshold set at 2 cases per configuration and the minimum acceptable PRI consistency cutoff threshold at 0.75. Configurations that do not meet these requirements will be neglected.As shown in The first category of hazard was potential electrical contact, as shown in TQCA was performed to summarize the corresponding visual patterns, as shown in the As shown in Numerous literature and statistics/reports indicate that a large part of unsafe behaviors that lead to accidents can be mainly summarized as failure of personal protective equipment (PPE) ,30,33. AThe first PPE failure hazard was recorded in safety inspection standards database as “during the hanging basket construction of outdoor glass curtain wall, the workers did not wear safety helmet as required”, as shown in In this hazard scenario, the AOI-A is the area above the worker’s chest, which contains the information that the worker is not wearing a helmet and is the core area of this hazard; corresponding to the AOI-A, the AOI-B is the area below the worker’s chest, which provides the information to determine the location and status of the worker; the AOI-C is the area of the outdoor glass curtain wall hanging basket operation, which implies a certain risk of falling objects to the workers below it. The results of condition necessity test are shown in The visual patterns between these AOIs were further analyzed in the following configuration analysis. According to the TQCA analysis was performed, and the results of the intermediate solution are shown in the The first strategy corresponds to the AB/ABC/ACB/AC configuration, in which participants will first target the area where the person is located, i.e., AOI-A, during the observation process, and focus on whether the construction workers wear personal protective equipment such as helmets in accordance with safety regulations, and then observe the surrounding environment and other components to complete a comprehensive judgment of the hazard. The second strategy corresponds to configuration CA/CBA/CAB/BC. Because of the existence of hanging baskets and high work situations in this scenario, participants’ feedback will first associate the potential risks of high work and falling objects, and then focus on workers who are not wearing helmets, thus completing the identification of hazards.The second PPE failure hazard was recorded in safety inspection standards database as a “violation of safety operation regulations due to the absence of safety belts on workers performing work at heights”, as demonstrated in In this hazard scenario, the AOI-A is the area where the workers working at height on the scaffold are located, contains the information that the workers are not wearing safety belts, which is the core components constituting this hazard; the AOI-B is the top area of the scaffold constituting the working environment at height, which is directly adjacent to the workers in space, and contains the clues for judging the location and status of the workers; the AOI-C is the middle support area of the scaffold, which helps determine the stability and structural soundness of the scaffold. The condition necessity test results were shown in The AOI-A is the only necessary basic AOI condition of the outcome, which contains the locations where worker in the construction site scene. This indicates that the area where worker is located is a necessary station in the visual scan path and the worker’s behavior or state is the primary area of attention allocation when identifying human-related FFH  hazards. The participants’ attention showed a very clear decreasing trend among the three AOIs, with PPE Failure in AOI-A, and the information of working at heights was contained in AOI-B receiving more attention. According to TQCA intermediate solution was shown in the The results shows that most participants chose the observation pattern of observing multiple AOIs in sequence before making judgments, presenting a high response accuracy rate.As shown in It is worth noting that in the two different visual paths, the areas of charged objects (A) and wires (B) are both necessary conditions for participants to successfully recognize hazards. However, the results of heat maps and post-experiment interviews with participants showed that they were more concerned about the intersection of (A) and (B). On construction sites, the most common electrical fires come from the connection of energized wires to equipment ,56, whicTherefore, the current research results show that when recognizing unknown scenes with potential electrical contact hazards, compared with energy-releasing source, giving priority to the intersection that considers the focus of attention among the components is more consistent with the cognitive patterns of safety-experienced construction workers, which supplements and revises the visual path generalized in previous visual research. Computer vision technology should pay more attention to the definition and feature extraction of the intersection areas to enhance the hazards recognition ability and efficiency in potential electrical contact hazard scenarios, as this may reflect the interaction between the two common components of energy-releasing source and wires. As RBC and gestalt model suggests that humans can identify hazards based on the spatial relationships of different elements and considering the extent to which they “deviate from the prototype” . FurtherBased on the results of data analysis, combined with post-experiment interviews, there are two strategies for participants to observe and recognize Hazards #2 and #3: (1) “Construction worker-PPE-construction work environment”. The corresponding specific visual search paths are shown in Solution #2-1 in Safety training provides workers with the knowledge base and long-term memory of safety regulations that guide workers to the most likely interpretation and identification of a given scenario and generate perceptual goals. Construction workers are searching for hazards in accordance with this paradigm, which is the “top-down” model in psychology. The human-object-environment strategy described above is also consistent with the requirement in [OSHA]  that safEven though the purpose of safety training is to reinforce long-term knowledge and enhance the effect of “top-down” inspection, due to the heavy construction workload, workers’ general perception starts from trivial signs and follows “heuristic” reasoning ,62 to deInterestingly, the results of the current study show that both strategies correspond to a fairly high correct rate of hazard recognition, without presenting a clear superiority or inferiority. However, it can be confidently concluded that the high accuracy rate corresponding to the normative interpretation means that the hazard recognition strategies taught in the safety training are effective, which verifies the positive effect of safety training on safety management. Safety training enables individuals to recall the requirements of safety regulations in construction scenarios, and consciously perform corresponding safety inspection and CHR. It is worth noting that although the “scene-associative” visual cognitive strategy appears to be less efficient than the “norm-guided” approach in targeting hidden areas, they both exhibit high levels of correctness, suggesting that the “scene-associative” may have potential implications for safety training. Specifically, the scenario-associative strategy is more reflective of worker experience, and although there may be significant internal individual variability, the overall consistent strategy presented helps to examine inappropriate instructional content that may be contrary to subjective human experience and habits in traditional construction safety training design . QualityIn addition, these two strategies also have enlightening significance for the development of computer vision in hazard recognition. For example, the paradigm of human interpretation of safety specifications and the top-down visual cognitive strategy can be referred to learn how to accurately map the content in safety specifications with inherent complexity in specific scenarios , thus enConstrained by the limitations of the analysis method, the construction industry study failed to accurately capture the temporal sequential visual patterns of CHR. This study introduces the TQCA method to summarize the visual sequence configurations with high identification correctness among all participants’ visual data, and summarize their strategies in combination with post-experiment interviews. The QCA method is highly applicable in revealing the influence of complex relationships among multiple antecedents on the results, given its ability to integrate the advantages of qualitative and quantitative analysis. On this basis, TQCA further extends the temporal dimension. By standardizing the encoding and analysis of visual sequences, TQCA substantially reduces the uniformity defects and substantial information loss caused by simple clustering  and neurThis study extends and deciphers the mechanism of applying RBC and gestalt model to the construction hazard recognition. Construction industry research has long considered hazard as a combination of individual components  , but theThis study aims to identify the temporal visual patterns exhibited by construction workers during their visual searching process and to explore the cognitive strategies of CHR reflected by these identified visual patterns through an eye-tracking experiment with real construction scene pictures as the background for CHR. The results show that: (1) In the potential electrical contact hazards, the intersection of the energy-releasing source and wire that reflected their interaction is the cognitively driven visual area that participants tend to prioritize; (2) in the PPE-related hazards, two different visual strategies, i.e., “scene-related” and “norm-guided”, can usually be generalized according to the participants’ visual cognitive logic in the recognition of PPE hazard, corresponding to the bottom-up (experience oriented) and top-down (safety knowledge oriented) cognitive models. This research furnishes a novel paradigm for the identification of visual patterns and the interpretation of CHR strategies from a cognitive perspective, as well as complements the RBC and gestalt model in visual cognitive theory, thus contributing to provide viable practical guidelines for the design and improvements of construction safety trainings and theoretical foundations of computer vision techniques for CHR.There are still some limitations of this study that need to be considered. First, the hazard scenes were presented on the monitor in the form of 2D pictures, and although the material was derived from photos of the construction site, there was a gap between the perception and the real construction site. Second, the types of hazards involved in this experiment were limited to three. However, there are many types of hazards involved in construction projects, even including combinations of multiple hazard types. Therefore, the visual recognition strategies obtained in this study may not be applicable to other hazard types. Third, two parts of experiments, A and B, were designed in this study. However, the observation time of 3 s per picture in Part A was not sufficient to form a reliable visual strategy. Although this design utilized principles such as priming effects and working memory (short-term memory), it could be improved in subsequent studies. In the end, the practical implications of this study including the development of hazard recognition devices and employee safety training need further demonstration.Based on the above limitations, this study suggests four potential valuable directions for future research. First, introduce virtual reality or augmented reality technologies into the research field of visual search sequence. Future studies may consider trying to use immersive and realistic reproduction of 3D construction scenes for the study if the technology allows. As a result, the data obtained from the study will be more realistic and reliable. Next, continue to expand the types of hazards involved in the experiments. Future studies are recommended to select more hazard scenarios and sample datasets to confirm the results and further explore the relationship between different hazard types as well as hazard recognition strategies. Then, in future studies, longer observation times for individual hazard scenes could be considered, thus, allowing participants to form strategies in a single observation. At last, researchers need to verify the practical implications of our findings through further experiments. For example, researchers are recommended to develop hazard recognition devices based on the visual cognitive strategies and select sample construction project to explore the practical value of this study for employees’ safety training design.


Multiscale brings great benefits for people to observe objects or problems from different perspectives. Multiscale clustering has been widely studied in various disciplines. However, most of the research studies are only for the numerical dataset, which is a lack of research on the clustering of nominal dataset, especially the data are nonindependent and identically distributed (Non-IID). Aiming at the current research situation, this paper proposes a multiscale clustering framework based on Non-IID nominal data. Firstly, the benchmark-scale dataset is clustered based on coupled metric similarity measure. Secondly, it is proposed to transform the clustering results from benchmark scale to target scale that the two algorithms are named upscaling based on single chain and downscaling based on Lanczos kernel, respectively. Finally, experiments are performed using five public datasets and one real dataset of the Hebei province of China. The results showed that the method can provide us not only competitive performance but also reduce computational cost. Clustering is one of the vital data mining and machine learning techniques, which aims to group similar objects into the same cluster and separate dissimilar objects into different clusters . It is sThe scale can be equivalent to the following concept: generic concept, level of abstraction, or perspective of observation; the same problem or system can be perceived at different scales based on particular needs . That isFrom the current research situation, multiscale clustering has been widely studied in various disciplines. However, from the analysis of the attribute type of data, most of the research studies are only for the numerical dataset, the quantitative analysis, and prediction of the data, but there is very little qualitative analysis about nominal dataset. Most of the datasets use characters to represent attribute values and do not have the properties of numbers. Even if they are represented by numbers (integers), they should be symbols and cannot be analyzed quantitatively. To study the nominal dataset, not only the complex data characteristics need to be obtained but also the proposed method needs to have some flexibility.The main contributions of this paper are as follows: (1) a multiscale clustering approach for Non-IID nominal data is proposed by introducing unsupervised coupling metric similarity; (2) combined with the scale-transformation theory and the idea of condensed hierarchical clustering, a scale calculation method based on a single chain is proposed to transform the clustering results from benchmark scale to target scale; and (3) combining the scale-transformation theory with Lanczos interpolation idea and based on the split hierarchical clustering idea, the Lanczos kernel-based downscaling algorithm was proposed to carry out multiscale clustering for the Non-IDD nominal datasets.The rest of this paper is organized as follows. k clusters such that each cluster must contain at least one element. The k-means algorithm proposed by MacQueen in 1967 is the most classical representation of the partitioning method [k members and applied it to collaborative filtering tasks [Clustering has attracted more and more attention from researchers and can be applied to many fields, such as time series analysis , 10, brag method , and thag method . Frey ang method . Differeng tasks . In 2015ng tasks . Spectrang tasks  originatng tasks  for the ng tasks  and usedIn 2014, Saffarzadeh et al. used the multiscale linear algorithm to analyze retinal images to determine whether eye lesions occurred . In 2015In clustering, we need to evaluate the dissimilarity among objects by using distance measure . MinkowsTo facilitate the discussion in the remainder of this paper, CMS is reviewed briefly in this section. CMS measures the similarity of two objects by capturing both the intra- and inter-attribute coupling relations of objects, where the former characterizes the coupling similarity between the frequency distribution and the value of attribute and the latter aggregates attribute dependencies between different attribute values relationship by considering the intersection of the condition attribute values co-occurrence probability of the different characteristics .A and B on attribute j is SIa  and is defined as follows:p=|N(Aj)|+1, q=|N(Bj)|+1, Aj represents the value of object A on attribute j, Bj represents the value of object B on attribute j, N(Aj) represents is the set of objects whose values of attribute are Aj, and |•| represents the number of the set.(intra-attribute similarity). The intra-attribute similarity between two objects Aj and Bj on attribute j with other attributes is SIe  and is defined as follows:d represents the number of attributes in dataset, rk|j is the weight of each attribute k to attribute j, and Sk|j represents the inter-attribute similarity candidates with attribute k and is defined as follows:Wk=VkN(Aj)∩ VkN(Bj), where VkN(Aj) is the set of values of attribute k for all objects in N(Aj) and Wk consists of those attribute values of attribute k which co-occur with both Aj and Bj, Wki is the ith element of Wk.(inter-attribute similarity). The inter-attribute similarity between two values of attribute A and B is S and is defined as follows:βj represents the weight of the coupled metric attribute value similarity of the an attribute j and Sj is defined as follows:α is the weighted harmonic mean of inter-attribute similarity and intra-attribute similarity. Different α reflects the different proportions of the intra-attribute similarity and inter-attribute similarity in forming the overall object similarity.(coupled metric similarity). The coupled metric similarity (CMS) between two objects Throughout in this paper, we use CMS to measure the similarity of two objects.The multiscale clustering framework proposed in this paper is shown in α, β ≤ ij. (line 5). The Laplacian matrix be calculated in line 5–10. The value and vector are computed in line 11, where N is the number of cluster and set in advance. The core and label of cluster are spliced to form Rcenter (line 14).Firstly, according to the probability density discretization method , the proAfter the clustering benchmark-scale dataset is completed, the cluster center of big-scale dataset can be deduced from the cluster center of the benchmark-scale dataset. In this paper, inspired by the idea of condensed hierarchical clustering, an upscaling algorithm based on CMS (UACMS) is proposed (line 2–4). Its basic ideas are as follows: each cluster center of the benchmark scale was taken as a cluster, and the CMS was distance measured, and the two nearest clusters were merged into one until the termination condition was reached (line 5–9). The specific process is as The downscaling algorithm based on Lanczos (DSAL) obtains the cluster center of the small-scale dataset from the cluster center of the benchmark-scale dataset, and the process is exactly opposite to UACMS in In this section, we compare our method with classical methods: k-modes and the spectral clustering that are based on 5 measures  and real datasets (renkou for short) were used for experimental verification, as shown in The NMI values of the algorithm UACMS in this paper and the six comparison algorithms on each dataset are shown in To facilitate comparison, the MSE value of seven different algorithms in the dataset Brc was reduced to 40% of the original value, as shown in In conclusion, through experiments, this section verifies that the proposed algorithm (UACMS) is superior to the other six algorithms in the clustering result indexes  on most datasets. In addition, the biggest advantage of UACMS is that the runtime of UACMS is significantly shorter than that of the comparing algorithms, and it does not change much along with increasing data volume. This is because the UACMS deals with the knowledge on the benchmark-scale dataset rather than the original data. As a result, UACMS is available and efficient.To facilitate comparison, the MSE values of six different algorithms in the dataset Brc are reduced to 40% of the original value, and the final MSE values of all algorithms are shown in The F-score values of DSAL and the comparison algorithms are shown in The runtime of the DSAL and the 6 comparison algorithms is shown in This section verifies that the proposed algorithm (DSAL) has obvious advantages in the external indicators (NMI and F-score) of clustering results on most datasets. Compared with the other algorithms, the DSAL's internal evaluation index MSE has a slight advantage. In addition, the biggest advantage of DSAL is that its runtime is significantly shorter than other algorithms, and it does not change much along with increasing data volume. This is because DSAL deals with the knowledge on the benchmark-scale dataset rather than the original data. Therefore, DSAL is available and efficient.In this paper, a multiscale clustering algorithm based on coupling metric similarity is proposed, multiscale data mining is carried out for the multiscale nominal datasets with non independent and identical distribution, and a scale conversion method based on the benchmark-scale clustering results is proposed: the scale estimation method based on single chain UACMS and the scale estimation method based on Lanczos kernel. The experimental results show that proposed framework is efficient and effective on the datasets whose attributes are obvious multiscale properties.In future work, we mainly focus on two aspects: (1) we are applying multiscale theory to frequent itemset mining and (2) the practical application of our study is worthy of attention, and we will consider applying multiscale clustering to collision detection and rule detection based on previous research studies.


The objective of the present study is to describe the stress and displacement patterns created by clear aligners and composite attachments bonded with the acid-etch technique on the labial surface of the maxillary first upper molar during its distalization. Maxillary molar distalization is a clinical orthodontics procedure used to move the first maxillary molar distally. The procedure is useful in patients with some Class II malocclusion allowing the first molar to move into a Class I relationship and the correction of associated malocclusion features. Three finite element models were designed to simulate the alveolar bone, molar tooth, periodontal ligament, aligner, and composite attachments. The first model had no composite attachment, the second model had a vertical rectangular attachment, and the third model had a newly designed attachment. A loading method was developed that mimicked the aligner's molar distal movement. PDL was set as a viscoelastic material with a nonlinear mechanical response. von Mises and maximum principal stresses and tooth displacement patterns were analyzed using dedicated software. All the configurations showed some form of clockwise rotation in addition to the distal movement. The crown portion of the tooth showed maximum displacement in all three models; however, in the absence of attachment, the root apex moved in the opposite direction which was compatible with uncontrolled tipping movement. Simulations with attachments exhibited the best performance regarding the movement patterns. The third group, with the newly designed attachment, exhibited the best performance concerning stress distribution  and higher stresses in the periodontal ligament and tooth. Incorporating a vertical rectangular attachment in a clear aligner resulted in the reduction of mesiodistal tipping tendency during molar distalization. The third model was the most efficient considering both displacement pattern and stress distribution. The level of stress generated by the third model needs to be further investigated in future studies. Class II malocclusion represent a large and heterogeneous group of malocclusions. Based on sagittal  dental and skeletal variables, Moyer et al. identified 6 Class II subgroups . Type A Different appliances have been used for upper molar distalization, the most common being the headgear that uses extraoral traction that has several advantages but requires significant patient cooperation to be effective . AlternaIt has been suggested that the force system generated by clear aligners, the most recently introduced class of orthodontic appliances, can mainly tip or intrude teeth but pure translation is not possible, at least theoretically . HoweverIn a retrospective clinical study, molar distalization presented the highest accuracy, approximately 87%, compared to incisor torquing and premolar derotation . The corFinite element methods have been employed to assess the biomechanics of bodily tooth moment with aligners and the role of composite attachment in displacement patterns –17. GomeThe present study aims to describe, using a FE model, the stress and displacement patterns generated by aligners and auxiliaries' composite attachments during upper molar distalization and the effect of a new composite attachments' shape and orientation in controlling this movement.This research was conducted at the Department of Orthodontics, Faculty of Dentistry, Near East University (Northern Cyprus).st molar. The third model was with the guideline attachment positioned on the buccal surface of the first maxillary molar.Three FE models were developed to simulate the alveolar bone, teeth, periodontal ligament (PDL) aligners, and attachment . The firTeeth, comprising the crown and the root, were designed based on ideal anatomy and position, with a mesiodistal angulation of 5.73 degrees, and labiolingual inclination of −11.3 degrees . PDL wasModel detail verification and convergence tests are possible with surface modelling tools (Surface-First Approach) for parametric modelling. However, we have used mesh surface modelling (Mesh-First Approach) to get highly detailed and realistic organic 3D models that cannot be achieved by parametric surface modelling. The software that we have used can import the mesh models (.stl files) and perform solid modelling and analysis. This method has the advantage of working on highly realistic 3D models compromising the ability to find the convergence point. However, since our models are highly detailed and the number of mesh nodes is far beyond any possible convergence point, we assume that we overcame that disadvantage of the Mesh-First Approach method.The physical properties of each structure, apart from the PDL, were described by using a linear elastic model. The alveolar bone and teeth were modelled as an isotropic nonhomogenous material with a linear elastic mechanical response. It is important to select individual material properties that align with the study goals to obtain accurate results in the region of interest . In the y-axis represents the sagittal plane with the positive direction being toward the mesial surface of the tooth and z-axis represents the vertical dimension with the positive direction toward the apical part.With regard to the coordinate system adopted in the present study; Bonded contacts, corresponding to a perfect rigid union (no degrees of freedom) between contact surfaces, were used to join the spongious and cortical bone, cortical bone-PDL, and tooth-attachment interface. Tooth and PDL were relatively constrained by bonded contact, which only allows small sliding movements between joined nodes. Also, the bone extremities were fixed in every direction  . The inty (−) axis, z (−/+) axis, and x (−/+) axis in the study to avoid any dependencies on force direction and calculations for anchorage and to prevent any potential differentiation in the future studies. Movement can be described as 0.15 mm displacement along the y (+) axis. The load was introduced by moving the tooth distally by 0.15 mm. To generate a loading condition, an initial penetration between the target tooth and the aligner is necessary. This loading condition described here is the opposite of what occurs in a clinical setting, where the aligner is thermoformed in the printed model with the maxillary first molar already distalized and the force system that results in tooth movement is produced by this mismatch.The aligner was restricted along the von Mises stressTension-compression pattern at the PDLDisplacement patternOutcome analysis in this study included the following:Displacement magnitude, distribution of von Mises stresses on the tooth, and maximum principal stress on the PDL, after application of a 0.15 mm displacement at the level of the first upper molar, are presented in Figures 5In the present study, negative sign for the maximum principal stress analysis indicates compressive stresses and positive sign, tensile stresses. In the first group, without attachment, the tensile stresses were higher in the cervical half of the mesial root surface (6.5 MPa) and cervical third of the distal root surface. Highest compressive stress (−0.43 MPa) was concentrated at the distobuccal aspect of the distal root. Compressive stresses were observed in both the mesial and distal aspect of the apical part of the palatal root, supposedly due to the rotation of the tooth . When a von Mises stresses at the tooth level predicted by the FE models of the first maxillary molar for the three groups and the displacement magnitude are presented in Figures The maximum displacement was observed at the crown level for all the groups . The movy-axis, and to the highest undesired movement, the palatal root was displaced mesially (−0.002 mm) suggesting uncontrolled tipping movement (y-axis was obtained with the guideline buccal attachment, which showed 0.13 mm of translation at the coronal level, 0.1 mm at the furcation level, and between 0.07 and 0.08 mm at the root apex of all three roots. Displacement obtained with the vertical rectangular buccal attachments showed 0.13 mm of translation at the coronal level, 0.09 mm at the furcation level, and 0.05 mm at the level of each root apex. The lowest tooth displacement was obtained with the standard aligner configuration i.e., without attachments, showing 0.12–0.13 mm of translation at the coronal level, 0.076 mm at the furcation level, and between 0.01 mm at the level of each root apex (Figures The standard aligner led to the lowest desired translation on the movement . The max Figures . In the  Figures .This result can be related to the different angles between the attachment active surface and the tooth. Further studies should also investigate the effect of the attachment positioning criteria on the tooth movement, focusing on the amount of active surface of the attachment.Despite the increasing popularity of clear aligners, a discrepancy is often observed between the actual outcomes and the planned orthodontic movements in virtual setup , 26. ThiAligners alone are not suitable for obtaining bodily movement as demonstrated for the palatal and labial translation of the upper incisor tooth . AttachmThe effectiveness of attachments in producing bodily tooth translation has been demonstrated in previous FE model studies –17, 24. The results of the present analysis suggest that uncontrolled tipping occurred when aligners moved the tooth in the absence of attachment. The addition of a vertical rectangular attachment resulted in a distal movement of the apexes of the roots. Still, the maximum displacement was observed at the crown level for both groups with an attachment, suggesting some degree of mesiodistal tipping. Principal stresses were determined at the periodontal ligament. In the third group, with guideline attachment, the stress was distributed more uniformly through the length of the root of the tooth, showing a pattern seen during maxillary first molar translation . In all Compared to other experimental models, FE analysis considers PDL so the assignment of the tissue properties can influence the stress values and distribution patterns as demonstrated by previous reports. In general, the linear model can underestimate PDL principal stresses and von Mises stresses at the root and overestimates them at the mid-root location . We did The current simulation is limited to the stress and movement analysis in the sagittal plane. Future simulations should consider other planes. Clinical experience suggests that the aligners can effectively control mandibular divergence during molar distalization . This isFurthermore, in the present FE model, the analysis is limited to a single tooth. The results assume that the first molar has an ideal angulation and inclination and normal marginal bone levels. Most of the FE studies on clear aligners are limited to a single tooth, or at times, a segment of the dental arch and only a few have established complete dental arch models. Previous research has shown that the extension of the segment included in the analysis influences, although to a small degree, the biomechanical response of the PDL . This isThe results of this simulation are limited to the analysis of stress and displacement patterns during initial tooth movement. However, tooth movement is a dynamic long-term process accompanied by an alteration of the force system and mechanical response of the tissues. Tooth movement and force generated by the aligners were maximal at the beginning of the process and quickly decrease . The chaFuture FE models might take into consideration the effect on the entire arch and the dynamic nature of tooth movement, and experimental studies that verify the reliability of the present FE model should be carried out in the future.This FE analysis was developed to assess the effect of different attachment configurations on the efficacy of bodily movement of the upper maxillary molar. The results show that configuration without an attachment and with a vertical rectangular attachment produced inclination of the molar in the mesiodistal direction while the guideline attachment produced stress and displacement pattern that most resembles bodily movement.


Polymeric nanocapsules have gained more and more interest in the medical sciences. Their core-shell structure offers numerous advantages, especially regarding their use as drug delivery systems. This review begins by presenting the different intrinsic sources of the instability of nanocapsules. The physical and chemical potential instabilities of nanocapsules reduce their shelf-life and constitute a barrier to their clinical use and to their commercialization. To overcome these issues, lyophilization is often used as a process of choice in the pharmaceutical industry especially when labile compounds are used. The state of the art of lyophilization nanocapsules is reviewed. The formulation properties and the process parameters are discussed for a complete understanding of their impact on the stability and storage of the final dried product. To assess the quality of the dried product, various characterization methods are also discussed. Over the last decades, nanoparticles have gained great attention in medical sciences ,2,3 espeNanoparticles and more specifically nanocapsules (NCPs) are usually produced in aqueous suspension forms. The chemical and physical instabilities of such carriers in aqueous media are the major challenge. These instabilities constitute a barrier to their commercialization and do not ensure a long-term stability. To overcome the chemical and physical instabilities, the immobilization of the molecular mobility of the constituents of nanocapsule system is required. This immobilization can be achieved after drying ,39,40,41Drying is one of the common unit operations in pharmaceutical industries permitting, through one or more phase transformations, to remove solvents  from liquid drug formulations in order to convert them into solid forms. The dry form allows to preserve their prime properties through the intended shelf-life. So, the obtention of solid-state nanocapsules is the main objective of lyophilization because it leads to the immobilization of the components of the formulation, namely the active substances, NCPs and the ligands if they are present at the surface of NCPs.In this article, we will focus only on nanocapsules with an oily core. We will review the different instability sources of NCPs in aqueous medium and discuss why drying and more particularly lyophilization is the most convenient and applied process. Although lyophilization is the most suitable process, it can be nevertheless a source of stress at each stage of the lyophilization cycle. In order to overcome the stresses and to be successful at freeze drying nanocapsules, the impact of the formulation and the process is reviewed and discussed.First of all, it is important to point out clearly the different intrinsic sources of the instability of polymeric NCPs. This instability can be either chemical or physical or both.The physical and chemical instabilities cited in The chemical instability of NCPs is mainly related: (i) to the hydrolysis of the polymer material forming the shell, (ii) to the instability of the entrapped drug, (iii) to the instability of thermosensitive ligands grafted at the surface of NCPs. The physical instability is often due to the aggregation and/or the fusion of NCPs. This constitutes a major obstacle to the storage in aqueous media. The drying process is therefore necessary to improve the stability of NCPs if only one of these instabilities is present.As the particle size of a suspension sample decreases down to the nanoscale, the surface to volume ratio and the surface energy increase. In the same way, NCPs tend to be inherently thermodynamically unstable and thus subjected to physical instability resulting in an aggregation and/or fusion of particles . As a coNCPs are usually formulated into aqueous media. The hydrolysis of the polymer material forming the shell is the most common source of chemical instability ,48. IndeIn The chemical reactivity of the encapsulated drug and the thermosensitive ligands of the functionalized at NCPs surface can also contribute to the chemical instability of the NCPs. The encapsulation of potentially unstable drugs such as peptides, proteins, enzymes, or other active substances may be delicate ,56,57,58It can be concluded that the physical and chemical instabilities of NCPs in aqueous media is a real challenge to be overcome. They are constantly prone to being destabilized, which limits their use. Another compromising limit is their reduced shelf-life. Several studies on the storage of nanosuspensions showed that their shelf life can be very low: suspensions of indomethacin-loaded NCPs are stable for 7 months, suspensions of diclofenac-loaded NCPs for 8 months, and suspensions of indomethacin-loaded nanospheres for 6 months . HoweverTo improve the stability and the storage conditions of nanoparticulate systems, freezing is widely used. Current examples which illustrates this preservation mode are mRNA-lipid nanoparticle COVID-19 vaccines of which the storage temperature is very low ,65,66. TTherefore, converting NCPs suspensions into a solid form seems to be an obvious solution. For this purpose, it is therefore necessary to dry the product in order to remove water and to obtain dried nanocapsule product. This strategy would significantly improve the chemical and physical stability of NCPs. Different drying methods of NCPs have been reported in the literature such as spray drying ,68,69, sFreeze drying, also known as lyophilization, is the most employed process for manufacturing pharmaceutical products that are thermo-sensitive and unstable in aqueous medium to ensure stability and prolonged storage in the dried state. Lyophilization process is a desiccation process where the solvent is frozen and then removed by sublimation under vacuum. Concretely, freeze drying can be divided into three stages: freezing (solidification), primary drying (ice sublimation) and secondary drying (desorption of unfrozen water). g’), the collapse temperature (Tc), and glass transition temperature of the dried product (Tg) are considered as critical. These thermophysical properties will guide the selection of the process parameters to develop the lyophilization cycle and to obtain a dried product with the highest quality , the glass transition temperature of maximally cryo-concentrated solute . For solutes that crystallize, the temperature of the system must be below the eutectic temperature to insure crystallization of the eutectic mixture (Teu) [Freezing is the first stage in the lyophilization process. During this step, the preparation is cooled, and ice nucleation of pure water occurs. As the freezing process continues, more and more water molecules contained in the preparation begin to grow into ice crystals. This leads to an increase of the concentration of solutes thus inducing an increase of the viscosity which reaches values of 10re (Teu) . Supercop) needs to be controlled with a safe margin (2–5 °C) below the collapse temperature (Tc) or the glass transition temperature (Tg’) in the case of very unstable biomolecules. The collapse temperature is determined by the microscopic observation  heat is transferred from the shelf to the frozen solution. (ii) The ice sublimes and the water vapor formed passes through the dried portion of the product . At the end of the sublimation stage, a porous plug is formed. The pores correspond to the spaces that were occupied by ice crystals. During this stage, the pressure is reduced. Pikal et al.  recommention see  during pg.Secondary drying involves the removal of adsorbed water from the product. It concerns the unfrozen water which did not separate out as ice during the freezing stage. The molecular motion of water in the solid and its evaporation to achieve lower residual water may require a greater energy to tear them from the solid by imposing a higher temperature and a lower pressure than during the sublimation stage. To maintain the product in its glassy state, the product temperature must be kept below Tp).In conclusion of this part, for each stage, the process parameters necessary to develop a lyophilization cycle, the set temperatures applied must be as close as possible to the temperature of product to be freeze dried  and preserve the activity of the drug encapsulated . To achiAlthough lyophilization is the most suitable process, unfortunately, it may induce numerous stresses that could destabilize the nanocapsules. The stresses can occur at different stages of lyophilization and may affect the formulation and thus the stability of dried NCPs. For these reasons, the formulation has to be deeply studied before the lyophilization process. The freezing and primary drying stages can be aggressive for NCPs. During the freezing stage of the nanocapsule suspension, a phase separation occurs between the formation of ice and the cryo-concentration of the suspension in the interstis. The high concentration of NCPs may generate their aggregation or fusion . During To prevent the instability of NCPs induced at the different stages, two types of protectants can be used: cryoprotectants and lyoprotectants. Cryoprotectants are defined as excipients whose primary function is to protect the active constituent and NCPs during the freezing process, whereas the lyoprotectants stabilize them during both freezing and drying stages. In the lyophilization process, most of protectants used are sugars such as mannitol , trehaloPCL NCPs showed aggregation and the formation of macroscopic particles after lyophilization without cryoprotectant . For ovaw/v) with and without 1% NaCl was conducted and showed that the presence of NaCl inhibits the crystallization of mannitol, which remains in amorphous state during freezing with NaCl. Beyond the protectants role to protect the product over the process, they may also have an impact on the drying stages. Indeed, their presence in the formulation must be kept in mind because they may modify the collapse temperature (Tc) of the product. Such phenomenon can impact the product quality, increase the time of reconstitution and increase also the residual moisture content. PCL NCPs have been freeze dried with four different excipients: sucrose, glucose, PVP, and HPβCD. The determination of collapse temperature (Tc) by FDM revealed that these different formulations have different collapse temperatures [The immobilization of NCPs within a glassy cryo-concentrated matrix of cryoprotectant lowers the mobility of molecules and thus can prevent their aggregation and protect them against the mechanical stress of ice crystals. In general, the freezing step should be carried out below all the thermal events of the frozen sample to ensure its total solidification. Abdelwahed et al.  demonstreratures . The colw/v) showed a residual moisture content of 1.30%, whereas the collapsed formulation without cryoprotectant had a residual moisture content of 4.10%. According to the authors, NCPs with mannitol 10% (w/v) demonstrated a successful lyophilization regarding the characterization parameters and the preservation of porous structures of the freeze-dried cake observed by scanning electron microscopy.Depending on their type and on their concentration, protectants do not have the same level of stabilization. Different parameters of freeze-dried ovalbumin loaded chitosan NCPs were studied before and after lyophilization:  diameterw/v) and cryoprotectant (5 and 10% w/v). The best results were obtained with a NCPs concentration of 0.25% w/v and trehalose concentrations of 10% w/v, most likely due to the more adequate protection of the NCPs by the vitrified matrix of the cryoprotectant against the stress of the freezing stage [w/v of trehalose and fructose.The stabilization of NCPs not only depends on the concentration of the cryoprotectant, but also on the concentration of NCPs. Chitosan NCPs recovery of the initial properties upon lyophilization and reconstitution varied with the concentration of NCPs  and 5% (w/v) of PVA were stable with no significant aggregation upon lyophilization, with no cryo- or lyoprotectant added.To ensure the maximum stability, a stabilizing agent is often used in NCP formulations since they are colloidal systems. It should be localized at the nanoparticles surface. The use of a stabilizer in the formulation of NCPs suspension can improve their stability and prevent their aggregation. In general, stabilizers are used at a concentration between 2.5 and 10%. During storage, aggregation becomes an even more important stability issue. For these reasons, the selection of an appropriate stabilizer and at the right concentration are crucial parameters of stability . VariousNevertheless, the presence of surfactants during the lyophilization process does not always lead to a stabilization effect. Chitosan NCPs of docetaxel were freeze dried and reconstituted. Upon reconstitution, the NCPs showed an increase in the size value of 50–100 nm. However, those containing poloxamer showed a significant increase in their size, a result that suggested that poloxamer interferes in the lyophilization process probably by its crystallization during freezing .Freeze–thawing stability of PCL NCPs are prepared with 1.25% of PVA protectant and by using two oils with different melting temperatures (Miglyol: Tm −3.5 °C and silicone oil: Tm −100 °C). The freezing temperature of −50 °C applied solidified the miglyol and kept the silicone oil in a liquid state. The preservation of NCPs containing silicone oil in the liquid state was not improved by the freezing. The encapsulated drug must also be taken into consideration. During the lyophilization process, the drug release kinetics may be affected, as well as drug degradation or drug leakage may occur. NCPs prepared with PLA as polymer and benzyl benzoate as oil were freeze dried . Howeverg’), the collapse temperature of the formulation (Tc), the stability of the capsule and its encapsulated drug, and also the properties of the excipients used [After optimization of the formulation, it is necessary to use adequate lyophilization parameters in order to obtain a lyophilizate with high quality. The lyophilization process is divided is three main stages: freezing (solidification), primary drying (ice sublimation) and secondary drying (desorption of unfrozen water). Nevertheless, this process induces many stresses and can damage the product. It is therefore essential to understand the mechanisms inducing these instabilities at the different stages of the process. This permits to make an informed choice of the formulation and the process parameters. The critical formulation properties include the glass transition temperature of the frozen sample , four cooling procedures were applied: immersion in liquid nitrogen, at −196 °C, immersion in acetone/dry ice bath at −78 °C, and two ramps temperatures of 1 or 2.5 °C/min. The results of size particle, polydispersity index and ratio of NCPs size after and before lyophilization being near 1 show that these nanocapsules were very stable during all the freezing procedures [In another study, PCL nanoparticles were characterized during the freezing and lyophilization stages without cryoprotectant. It was observed that the lyophilization process was faster with slow cooling rates rather than with high cooling rates. At slow cooling rates, a small number of large ice crystals are obtained, whereas at high cooling rates, a large number of small ice crystals are obtained. Increasing the porosity and permeability of the dry matrix can lead to an increased sublimation rate, shortening the drying time ,98. For ocedures .However, the presence of a cryoprotectant can impact the nanoparticles during freezing. Depending on the type and the concentration of the cryoprectant used in the formulation, the stabilization of NCPs over lyophilization can be modified. During lyophilization of griseofulvin-lipid nanoparticles with xylose as cryoprotectant, the crystallization of the saccharide induced an irreversible aggregation . Lee et Freezing, being the first step in the lyophilization process, strongly influences the size and the shape of ice crystals, thus impacting primary and secondary drying. Usually, the optimization of the lyophilization process focuses on decreasing the time of the primary drying because it is the longest stage.g’ for a period of time [Annealing is a process stage in which samples are maintained at a specific subfreezing temperature, above T of time . Anneali of time . Anneali of time . Figure In addition, annealing can inhibit the formation of the skin layer on the top of the freeze-dried product, which increases the sublimation rate. Indeed, this skin is formed by the migration of cryoprotectants and nanoparticles during the crystallization of ice. This layer may slow down the transfer of water vapor during sublimation . Figure One can observe that the resistance increases with the increase of the dry layer thickness. Additionally, the resistance to water vapor transfer reduces significantly when annealing is applied. The lower resistance was observed with annealing at −10 °C. This result may be attributed to the fact that annealing generates an increase in pore size, therefore reducing the resistance to water vapor transfer during sublimation . FurtherAbdelwahed et al.  studied g’ of sucrose than of PVP. They also studied the impact of annealing on the secondary drying and showed that is it dependent on the type of cryoprotectant used: in the case of PVP, the annealing step did not slow down the secondary drying kinetic, whereas with sucrose, a longer kinetic was observed.The results demonstrated that the process which did not include annealing had the lowest sublimation rate for both protectants. On the contrary, annealed samples had the highest sublimation rates. Additionally, sublimation rates increased when the temperature of annealing was increased from −20 to −10 °C. Nevertheless, the increase of sublimation rates was not the same for both protectants because they have different glass transition temperatures. Indeed, the temperatures chosen for annealing were above the Tw/v) of mannitol was studied [g’ of the formulation is about −34 °C. Four different annealing temperatures from −5 to −25 °C during 1 h have been applied. An increase in the nanocapsules size ratio before and after annealing (SF/SI) was observed. For annealing temperatures of −25, −15, −10 and −5 °C, the corresponding size ratios were 1.15, 1, 1.68, 1.92, and 2.31, respectively. This demonstrates that an increase of annealing temperature leads to an increase of nanocapsules size. However, the freeze-dried preparations did not present any sign of collapse or shrinkage. It is important to point out that the morphological aspect of the freeze-dried product is not necessarily linked to a successful lyophilization.The influence of temperatures of annealing on particle sizes of chitosan ovalbumin-loaded nanocapsules prepared with 10%  on the other hand uses a lower vacuum and allows the analysis of hydrated specimens without any sample preparation. Therefore, ESEM enables the observation of lyophilized NCPs in a hydrated state. Transmission electron microscopy (TEM) allows to obtain high magnification images via an electron beam directed through the sample. This technique gives information about particle shape, and more specifically enables the observation of the membrane constituting the polymeric shell and measurement of its thickness. Another interesting, but non-electronic microscopic observation is atomic force microscopy (AFM). This technique generates images by scanning a cantilever over the surface of a sample. It provides nanoscopic three-dimensional images of the surface topography, heterogeneities and local mechanical behavior . This teDuring freeze drying microscopy (FDM), the sample corresponding to a droplet around 20 µL is first frozen under atmospheric pressure, followed by an increase of temperature and pressure. This technique enables the assessment of the collapse temperature of the dried structure. The collapse temperature is determined by visually recognizing morphological changes at the sublimation front of the sample .To reconstitute the lyophilized product, the same volume of water that had been removed should be added. Usually, a correct lyophilizate should be rehydrated immediately. However, in the case of collapsed formulations, a long reconstitution time can be observed. To achieve the re-suspension of lyophilized NCPs after the addition of water, manual shaking is usually used .The analysis of particle size after reconstitution is important to assess the stability of NCPs after lyophilization. The preservation of NCPs diameter after lyophilization is considered as a good indication of a successful process. Furthermore, the ratio of nanoparticles size before and after lyophilization can be calculated. A value close to one indicates the conservation of the size. On the contrary, a high ratio value shows an aggregation of particles . The parThe polydispersity index gives information about the distribution of NCPs size. The values before and after lyophilization can be compared in order to evaluate the conservation of nanoparticles distribution. The PDI is a dimensionless calculated number based on the mean particle diameter .The measurement of the zeta potential is useful to evaluate the state of NCPs surface and to detect any eventual modification after lyophilization. The zeta potential value is closely related to suspension stability and particle surface morphology . Its valThe measurement of the drug content before and after lyophilization is important to assess any leakage of the drug during the process. It can be measured by high performance liquid chromatography (HPLC) . After lFreeze-dried docetaxel-loaded chitosan NCPs were developed to evaluate their potential for intracellular delivery of docetaxel and their efficacy . For thiIn another study , lyophilThe stability of NCPs is strongly related to the residual moisture content of lyophilized product. This parameter is important to determine because it may influence the thermal and the structure properties of the lyophilized product. The residual moisture content can be determined by Karl Fischer titration or thermogravimetric analysis . HoweverAdditionally, the study of sorption isotherm of water is essential to determine the degree of hygroscopicity of the product, and also to assess the ease in the secondary drying . To condg’, the drying stages and storage should also occur below the Tg’. For this purpose, evaluating the Tg’ of the formulation by thermal analysis is essential. It can be performed by differential scanning calorimetry (DSC). Besides, this technique can be useful to evaluate the interactions between protectants and NCPs [As previously mentioned, the NCPs suspension should be frozen below the Tand NCPs . DSC alsand NCPs .The use of nanocapsules in drug delivery is well established. This review showed that the chemical and physical instabilities of nanocapsules constitute a major barrier to their clinical use and to their commercialization. The use of lyophilization becomes necessary especially when NCPs contain hydrolysable or thermolabile substances . Lyophilization is a multidisciplinary field. It requires deep knowledge of formulation, physical and chemical characterizations of the product and finally a deep knowledge of the whole process. In the literature, it has been shown that the formulation and the lyophilization process are intimately related and one impacts the other. In fact, lyophilization of nanocapsules is quite delicate because the process generates numerous stresses on these fragile systems. In order to withstand these stresses and perform an optimal lyophilization cycle, a convenient protectant at the right concentration can be used. The annealing can also be applied to shorten the duration of sublimation stage. The lyophilization of nanocapsules, when it is fully controlled could really revolutionize their use in the medical field by ensuring stability and a long-term preservation. Currently, the research is in progress in order to set up a continuous lyophilization to reduce the cost ,123.


This study aimed to evaluate in vitro performance refractive segmented EDOF intraocular lenses under polychromatic light using an optical bench that complies with the ISO 11979-2 Norm. The through focus modulation transfer function (TF-MTF) of the Femtis Comfort LS-313 MF15  IOL was evaluated for IOLs with three different base powers. The effect of the asymmetry of the segmented designs was evaluated with 3 different wavelengths and with polychromatic light at a 3.0 mm and 5.0 mm pupil diameter. It was demonstrated that the TF-MTF curves exhibit a bifocal profile that, in practice, results in an EDOF design. As a consequence of the LCA, the TF-MTF values in white light were lower than in monochromatic light. Images of the USAF test chart were obtained to confirm the prediction of the TF-MTFs. We found that Femtis Comfort is a bifocal low-addition IOL and this fact can result in an EDOF effect which was obtained previously in clinical trials. Moreover, we showed that the base power influences the IOL optical quality, which results as more effective for high powers (hyperopic eyes) than for low powers (myopic eyes). The LCA of the segmented refractive design was very low and presumably not clinically relevant. The surgical options for the correction of presbyopia have increased significantly in recent years. In fact, new designs of intraocular lenses (IOLs) come to the market responding to the growing demand by patients for spectacle independence for vision at intermediate distances, where classic bifocals do not provide good vision. One approach is the so called extended depth of focus (EDOF) IOLs. The American Academy of Ophthalmology working group published a consensus statement for these IOLs: an EDOF is a lens that provides an extension of focus that is at least 0.50 D wider than for a monofocal IOL at a visual acuity of 0.2 logMAR . There aIn this work we have performed the first comparative experimental study of the chromatic behavior of the Femtis Comfort IOL as a function of power, by using the through focus modulation transfer function (TF-MTF). Two different pupil diameters (corresponding to photopic and mesopic illumination conditions) were considered. Additionally, since this is a lens without revolution symmetry, we have investigated the differences between the TF-MTF along the sagittal and tangential meridians. These results have also not been previously reported in the literature. We studied the image quality provided by three different base power IOLs for different wavelengths separately  and also with white light. Considering that we live in a polychromatic environment, the knowledge of the polychromatic response of every IOL in an optical bench is important to surgeons to know its main features and to predict its clinical outcomes.In this study, three different Femtis Comfort IOLs of base powers 15 D, 20 D, and 30 D were studied and compared. The Femtis Comfort IOL is a refractive lens with an optical zone of 5.7 mm that includes a rotationally asymmetric near vision segment of Add = 1.5 D. It is made of a copolymer consisting of hydrophilic acrylates with a hydrophobic surface. The optic is biconvex, with an aspheric posterior optic to neutralize high order aberrations. Additionally, it has a plate-haptic design with 4 flaps for capsulorhexis fixation.The relative phase profiles of the different lens base powers are shown in Numerical simulations of the expected experimental TF-MTF provided by a segmented refractive IOL emulating the Femtis Comfort profile were first performed in order to identify the expected differences between the tangential and sagittal profiles. To this end, we employed a commercial ray tracing optical design software  in which all the elements of the optical bench were included. For this simulation we have considered a lens of 20 D base power and 1.5 D Add. Due to the lack of manufacturer’s data, we used typical values of other IOL models for the radii of curvature ® . A representation of the optical setup is shown in As detailed in an earlier publication , our expTo isolate polychromatic optical performance of the IOLs from the residual chromatic aberration generated by the optical elements in the optical bench, the optical setup was calibrated by measuring the LCA of the system without the IOL, and this result was subtracted from the experimental TF-MTF curves.As detailed in Ref. , TF-MTFsFinally, in order to evaluate the imaging performance of the IOLs in the model eye under polychromatic illumination, the test object has been replaced by the 1951 USAF resolution chart and the corresponding images were obtained at different vergences.To realize the differences between tangential and sagittal TF-MTFs, the first step was to obtain numerically the characteristic tangential and sagittal TF-MTFs of the segmented refractive design for a single wavelength (550 nm), and then compare them with the experimental results in the optical bench.Using data available from the Femtis Comfort, we performed the numerical simulation with Zemax in green light for a 20 D IOL base power. This merit function was computed for 3.0 mm and 5.0 mm pupil diameters. The corresponding experimental results are shown in the central column of The low-addition bifocal nature of the Femtis Comfort design is verified for all wavelengths. This behavior is also qualitatively preserved for both pupil diameters in each lens power.The TF-MTFs in The LCA was obtained from the corresponding TF-MTF curves as the difference, in diopters, between the blue (450 nm) and the red (650 nm) focal planes. The results are shown in Finally, A very clear correspondence of these images with the TF-MTFs shown in The purpose of this work was to provide objective evidence of the influence of the asymmetric design and different base powers on the polychromatic behavior of segmented refractive EDOFs. We have shown that the experimental TF-MTFs obtained independently in two perpendicular directions  can be used to predict the image quality of these types of IOLs by averaging these two components. In this sense, we obtained evidence not previously mentioned neither in the literature, nor by the manufacturer itself, that the combination of two powers in different sectors of the lens causes an overlapping of the tangential and sagittal TF-MTFs that favors an extension of focus, especially for small pupil diameters. However, the astigmatic-like images that can be observed in Our results confirmed that the EDOF Femtis Comfort is actually a bifocal IOL with an Add value of 1.5 D. In fact, the TF-MTFs we obtained for different powers and pupil diameters all showed a bifocal profile. This conclusion can also be obtained from the USAF test images see  since thA recent clinical study that reported outcomes of the Femtis Comfort  confirmsWe found the LCA of the Femtis Comfort in both foci is positive, as expected for a pure refractive design, although the amount of the LCA measured in all cases was lower than 0.5 D and no significant differences were obtained in the LCA for photopic and mesopic pupil diameters. Nevertheless, the TF-MTF values in white light were lower than those obtained with monochromatic light. The influence of the lens power on chromatic aberrations was numerically studied in eye models by Song et al.  working In another related work, Radhakrishnan et al.  measuredIn conclusion, to the best of the authors’ knowledge, this is the first study that reports experimental objective metrics for the Femtis Comfort EDOF MIOL with polychromatic light. We measured the sagittal and tangential TF-MTF for 3 different base power lenses under different wavelengths and white light, and two pupil diameters. We demonstrated that additionally to the low Add value, the segmented bifocal design gives the lens its EDOF character. In fact, we have shown that the image quality of this type of segmented EDOF can be explained by means of the average of the sagittal and tangential TF-MTFs.Despite the base power influencing the optical quality of this refractive EDOF IOL, the LCA was lower than 0.5 D independently of the base power and pupil diameter. Therefore, in the Femtis Comfort, the LCA presumably is not clinically relevant.


In this study, the information flow time arrow is investigated for stochastic data defined by vector autoregressive models. The time series are analyzed forward and backward by different Granger causality detection methods. Besides the normal distribution, which is usually required for the validity of Granger causality analysis, several other distributions of predictive errors are considered. A clear effect of a change in the order of cause and effect on the time-reversed series of unidirectionally connected variables was detected with standard Granger causality test (GC), when the product of the connection strength and the ratio of the predictive errors of the driver and the recipient was below a certain level, otherwise bidirectional causal connection was detected. On the other hand, opposite causal link was detected unconditionally by the methods based on the time reversal testing, but they were not able to detect correct bidirectional connection. The usefulness of the backward analysis is manifested in cases where falsely detected unidirectional connections can be rejected by applying the result obtained after the time reversal, and in cases of uncorrelated causally independent variables, where the absence of a causal link detected by GC on the original series should be confirmed on the time-reversed series. X and Y based on predictability and precedence [x and y, corresponding to variables X and Y, respectively. If the predictive error variance of y only from past y values is greater than the predictive error variance of y from both past x and past y values, then the variable X is said to cause variable Y, denoted F-test for significance of regression coefficients.Investigating causal relations between simultaneous recordings of variables is a common task in scientific fields as diverse as neuroscience , climatoecedence . As all x significantly improves the prediction of y . Analogously, we test the opposite direction A slightly different approach to test Granger causality that we will also use here is to test for predictive errors (PEGC) instead of testing for regression coefficients. It means that the null hypothesis of no predictability improvement is statistically tested against the alternative hypothesis that the inclusion of the knowledge of e spaces .To avoid the problem of spurious causal detections, especially in the analysis of electroencephalographic signals, Haufe et al.  have sugThe concept of time inversion testing is based on the intuitive idea, that if the first principle of Granger causality that the cause precedes the effect holds, then reversed role between a driver and its recipient can be expected for the time-reversed series, but can we really expect that? In , Paluš eF-test for Granger causality is only guaranteed for the normally distributed predictive errors of present values x and y, see e.g., [In this paper, Granger’s analysis of causality between two variables in the context of time reversals is numerically studied. We are mainly interested in the effect of time reversal on the change in the order of cause and effect. Three different Granger causality detection methods are used. They are applied to linear autoregressive processes for which the Granger’s causality is originally formulated. According to the literature, the validity of the ee e.g., . In thisAs we have already indicated, in addition to the effect of predictive error distribution, we are also interested in whether the type of used causal method plays a role. To find out, we numerically tested several ways to estimate Granger causality.Granger causality and three approaches for testing Granger causality are introduced in X and Y, represented by simultaneously observed stationary zero mean time series X to a response variable Y involves two linear models [y on the past x in the linear autoregressive model  , x,…,x(T)} X fails to Granger-cause Y if all F-distribution with p and X Granger-causes Y. To search for the causal influence in the opposite direction, i.e., Variable pSSRyx/T−p∼as.Fp,Td) model . Under ttatisticFX→Y=(SSRtatisticFX→Y=(SSRThe regression coefficients in –5) may  may 5) movations . Grangerp of VAR can be determined using a model selection criterion. For example, the Akaike information criterion [F-test for testing the submodel is meaningful if both the full and the restricted models are well-defined linear models. In fact, while the full model is of finite order, the reduced one is generally of infinite order. To eliminate potentially problematic consequences for Granger causality analysis, it can be recommended to estimate appropriate model order for the reduced model, rather than for the full model [The order riterion  and the riterion  are commll model .X does not Granger cause Y. This seems to fit definition of no Granger causality, when the variance of predictive error of y using only past of y cannot be reduced by also using the past of x [y is significantly improved by including the information of past x in a linear autoregressive prediction, i.e., X causes Y. Analogous testing procedure is applied to analyze the causal connection If all coefficients ast of x . The preast of x ,17. HereX about the future value of variable Y, and in Y about the future of X, is quantified by the Granger causality score [X helps to improve the prediction of Y. On the other hand, the values of X does not improve prediction of y, meaning that X does not Granger cause Y.The additional information contained in variable ty score ,18 definX and Y using the difference of the net Granger scores obtained from the original data, given as Let sed TRGC ,7 analyzX Granger causes Y and Y does not Granger cause X, then Winkler et al.  also shoX does not Granger cause Y. Analogously, the causal connection Y does not Granger cause X. We see that with this modification, we should also be able to detect bidirectional connection. Similarly to TRGC, the bootstrapping approach can be applied to perform statistical inference [Instead of the net Granger scores, we propose to examine the difference variable nference .We propose two versions of TRGC modification. The first one includes a statistical significance testing and is denoted as mTRGC. The second version is based on non-statistical evaluation of In addition, we test the combination of GC and mTRGC*, denoted GC+mTRGC*. A causal link is detected by GC+mTRGC*, if the causal link is found to be significant by GC and the detection is confirmed by mTRGC* subsequently.The introduced methods GC, PEGC, mTRGC, mTRGC*, and GC+mTRGC* will be applied to detection of causal interaction between two variables in numerical experiments without an influence of a common hidden variable, and measurement noise. The performance of all five methods is numerically examined on processes generated by a bivariate order-one AR model under considering seven different distributions of the predictive errors. Besides the normal distribution typically used for defining VAR, serially independent predictive errors are generated by a uniform distribution, triangular distribution, and a mixture of normal distributions. In addition, the predictive errors generated by the moving-average model, and quadratic moving-average model is used to analyze the impact of model assumption violations to the performance of the Granger causality detection methods. Moreover, the effect of instantaneous interactions is analyzed through generating correlated predictive errors. Causal relationship will be analyzed by all introduced methods on both originally generated time series and the time-reversed series.Causal independence : The predictive errors Condition B (uniform distribution): The predictive errors Condition C (triangular distribution): The predictive errors Condition D : Both predictive errors Condition E (moving average): The predictive errors Condition F (quadratic moving average): The predictive errors Condition G (correlation): The predictive errors The predictive errors Note that various parameters in conditions B–G were chosen to obtain the same means and variances of variables The investigation of causal interaction between variables was performed with generated time series of length Instead of a bootstraping method, the The performance of the Granger causality detection methods was evaluated by two rates: false positive (a type I error) and false negative (a type II error). A false-positive rate (FPR) is the proportion of all cases without causal links, where a test result incorrectly indicates the presence of a causal effect. The significance level The determined FPRs and FNRs for a model system were averaged according to a condition, sample size, and a testing procedure. The averaged rates of false results are presented in a and of the predictive error variances in the case of causally independent variables. Except for the condition F, the obtained FPRs for unidirectionally connected variables are independent of a value of the connectivity structure control parameter It can be concluded that GC is an exact test for the Granger causality. The presented FPRs obtained on the original time series are very close to the chosen significance level. This is true even for predictive error distributions that are different from the normal distribution which is usually required for the validity of Granger causality analysis. The only exceptions are the false positive results obtained under condition F, see The power of GC increases  with increasing sample size, see p) on the time-reversed series leads to the problem of endogeneity bias. In that case, the values …, …, Let us now look at the results of GC after application to the time-reversed series. It is worth emphasizing that the fitting of a VAR for unidrectionally connected variables was obtained by mTRGC*, we proposed to combine mTRGC* with GC. Our intention was to analyze a potential improvement of GC by using the results from the time-reversed series, on the original time series. The observed FPRs were similar to the FPRs obtained by GC for causally independent variables, except under the condition G. Since the highest number of correctly detected absence of a causal link occurred for correlated causally independent variables, the difference was expected. A significant number of the false positive detections by GC was rejected by additional applying mTRGC* for unidirectionally connected variables. Moreover, the observed FNRs by GC for unidirectionally connected variables did not change significantly after applying mTRGC*. As it was expected based on the previous results, many of correctly detected connections by GC for bidirectionally connected variables were rejected after additional application of mTRGC*. For the results, see In the case of stochastic data defined by autoregressive models, the change of the direction of causality after the time reversal is investigated by different Granger causality detection methods. The clear effect of a change in the order of cause and effect is widely observed by mTRGC and mTRGC*, while GC and PEGC observe a clear reversal of causality only under specific conditions. Unambiguously opposite direction of causal link was detected by GC and PEGC on the time-reversed series only when the product of the connection strength and the ratio of the predictive errors of the driver relative to the recipient were below a certain level. If it was above that level, bidirectional causal link was mostly detected by GC and PEGC. The bidirectional causal detections after time-reversal of unidirectionally causally connected variables might occur as consequence of the endogeneity bias. Indeed, components of the backward predictive errors were correlated on similar set of values of the connection strength and of the ratio of the predictive error variances for which bidirectional causal connection was detected. The set of values leading to such bidirectional detection even increased with increasing sample size.Although, in general, the methods based on time-reversal testing suffer from the inability to correctly detect bidirectional connections, they can serve to verify the results of GC. A falsely detected unidirectional causal connection by GC can be rejected by applying mTRGC* additionally. Moreover, the absence of causal link detected by GC on the original series should be detected also on the time-reversed series of uncorrelated causally independent variables.GC test turned out to be an exact test for Granger causality even for predictive error distributions that are different from the normal distribution. However, the assumption of no-autocorrelated predictive errors was crucial for validity of GC. Our results indicate that, even if a part of the model assumption is violated, under some circumstances, GC can still yield meaningful results. Finally, it should be mentioned that even if the autoregressive model fits the correlation structure in the data, spurious causalities could still arise if some relevant variables are not analyzed. The problem of a hidden confounding variable as well as measurement noise issues were not considered in this work.