Although conductive hearing loss can be corrected by surgery, the currently available clinical investigations cannot always diagnose the ossicular chain pathology underlying the conductive hearing loss, and even intraoperative findings can be equivocal. Acoustic analysis using finite element models (FEMs) can simulate the sound pressure change at an arbitrary site for each frequency. FEMs are used in acoustic engineering to simulate the frequency-dependent sound pressure distribution at discrete cells in a simulated model and analyze the effects of specific parameters on the audiogram. However, few reports have compared the numerical results obtained using FEMs with data from clinical cases. We used FEMs to simulate audiograms of the air-bone gap (ABG) for various ossicular chain defects and compared these with preoperative audiograms obtained from 44 patients with a normal tympanic membrane who had otosclerosis, middle ear malformations or traumatic ossicular disruption. The simulated audiograms for otosclerosis and attic fixation of the malleus-incus complex both exhibited an up-slope but could be distinguished from each other based on the ABG at 1000 Hz. The simulated audiogram for incudostapedial joint discontinuity exhibited a peak at around 750 Hz and a down-slope above 1000 Hz. In general, the simulated audiograms for otosclerosis, attic fixation and incudostapedial joint discontinuity were consistent with those obtained from clinical cases. Additional simulations indicated that changes in ossicular mass had relatively small effects on ABG. Furthermore, analyses of combination pathologies suggested that the effects of one defect on ABG were added to those of the other defect. These FEM-based findings provide insights into the pathogenesis of conductive hearing loss due to otosclerosis, middle ear malformations and traumatic injury.The middle ear transmits sound to the inner ear  The mammalian middle ear contains three bones  suspended by ligaments and tendons. The middle ear acts as a “bridge” that transmits sound vibrations between the tympanic membrane and oval window. Among patients with an intact tympanic membrane and an air-filled middle ear cavity, the main causes of conductive hearing loss with a large air-bone gap (ABG) in the audiogram are abnormalities of the ossicular chain (fixation or discontinuity) and the presence of a third window in the inner ear .Disorders that cause ossicular chain abnormalities include congenital malformations, otosclerosis, trauma and inflammatory diseases. During normal development, the three ossicles separate from the temporal bone and become linked . MalformConductive hearing loss can be treated by surgical reconstruction, but the operative difficulty depends on the location and severity of the defect and the presence of concomitant pathology. Inadequate knowledge of the underlying pathology can lead to the lesion being missed and the operation taking longer than expected. In fact, even detailed intraoperative microscopy cannot fully visualize the surgical field if the view is obstructed by cholesteatoma or the fracture line is in close proximity to soft tissue . TherefoPreoperative investigations include otoscopy, computed tomography (CT) and audiometry. Otoscopy is the most basic examination used to assess the condition of the middle ear and can detect middle ear effusion, negative pressure in the middle ear and increased mobility of the tympanic membrane. However, otoscopy provides only limited information about the continuity and vibratory properties of the ossicles because only the handle of the malleus is visible. The resolution of CT scanning has improved in recent years, which has enabled the ossicles to be visualized more clearly with this technique. However, ossicular fixation and complete or incomplete discontinuity of the ossicular chain are difficult to detect using CT. Audiological tests such as pure-tone audiometry and tympanometry can quantify the efficiency of sound transmission and the impedance in the middle ear, and the results of these tests are known to reflect middle ear pathology. In particular, pure-tone audiometry contains frequency-specific information that can be used to estimate microscopic and qualitative changes in pathology.There have been many attempts to infer pathology from the results of pure-tone audiometry, and this has contributed to clinical practice. For example, an up-sloping audiogram due to an elevated low-frequency threshold is typical of otosclerosis, and large increases in threshold at all frequencies are seen in patients with ossicular chain dislocation. However, the relationships between audiometry findings and underlying diseases have been inferred from clinical data, and the specific effects of each type of pathology on sound transmission efficiency have yet to be fully characterized. Therefore, preoperative pure-tone audiometry has limited ability to characterize the specific pathology affecting the ossicular chain.In view of the diagnostic limitations described above, we have focused on the use of finite element analysis (FEA) to evaluate the middle ear sound transmission system. Phantom simulations allow the visualization of nanoscale vibrations in arbitrary structures within the simulated middle ear, and the physical properties of these structures can be altered at will. Finite element models (FEMs) have improved over time and been applied not only to the middle ear but also to the outer ear and inner ear. The first FEM of the middle ear was published by Funnell and Laszlo in 1978, and their model of the tympanic membrane of the cat was shown to be consistent with experimental values . Since tThe aim of the present study was to construct FEMs that could simulate the pathogenesis of conductive hearing loss due to otosclerosis, middle ear malformation or trauma. We compared the results of our FEMs with data obtained from patients who had undergone surgery for hearing loss and whose pathology was known from the intraoperative findings. First, we evaluated the validity of a newly constructed FEM of a normal middle ear by comparing the results with previous reports. Then, we constructed models of ossicular sclerosis and incomplete ossicular discontinuity and compared the findings with audiograms obtained from real cases. Finally, we used FEMs to analyze the effects of changes in ossicular chain mass and complex pathologies. The results of our FEA show that, for each of the diseases that cause conductive hearing loss, the simulated audiometric pattern was generally consistent with the audiograms of actual cases. Based on the findings of this study, we suggest that the combination of pure-tone audiometry and FEA could be used to improve the preoperative diagnosis of the pathology underlying conductive hearing loss.K is the stiffness matrix, D is the damping matrix, M is the mass matrix, C is the coupling matrix, x is the displacement vector, p is the sound pressure vector, f is the external force vector, S denotes the structural component and A denotes the acoustic component. The ear canal and middle ear cavity were not included in the FEM. The present FEM excluded the middle ear cavity because a review of the literature indicated that the magnitude of the impedance of the middle ear cavity is negligible compared to the magnitude of the impedance of the tympanic membrane and ossicles; this allowed us to concentrate on the mechanically most important structures in the middle ear . The study included patients with malformation of the ossicular chain, traumatic ossicular chain disruption or otosclerosis, confirmed mobility of the stapes footplate and normal tympanic findings who underwent middle ear surgery at the Jikei University School of Medicine between April 2016 and March 2020. The diagnosis was made on the basis of the medical history , otoscopy findings, pure-tone audiometry and CT imaging and was confirmed at the time of middle ear surgery. Pure-tone audiometry was performed in a double-chamber anechoic room. All hearing tests were performed by an experienced audiologist who measured air conduction and bone conduction thresholds with masking as appropriate. Hearing tests were performed preoperatively using frequencies of 250, 500, 1000, 2000, and 4000 Hz. An otolaryngologist confirmed the details of the thresholds. The number of cases and age distribution by disease are presented in First, the validity of the newly constructed FEM was evaluated through comparisons with previously published data. To achieve this, we used the FEM to calculate the displacements of the malleus umbo and stapes footplate perpendicular to the structural plane during the simulation of an 80 dB SPL sound pressure applied to the tympanic surface. Then, the calculated values were compared with those measured previously in the living body or cadavers and with data published for other FEMs. We compared our simulation values for the measured displacement of the tympanic membrane (umbo) , the simNext, we investigated sclerotic pathologies . FEA wasTo simulate malformations in which the malleus and/or incus are fixed to the attic wall of the middle ear, we constructed FEMs with part of the upper surface of the malleus and/or incus set to non-vibration . The up-p = 0.0006), a sensitivity of 87.5% and a specificity of 82.6%.The common audiometric features of the above sclerosing conditions were up-sloping due to ABG expansion in the low-frequency band and a strong gradient change  at around 1000 Hz. The audiogram for footplate fixation (otosclerosis) exhibited an exponential slope after correcting for the Carhart notch by substituting the value at 2000 Hz for the average value of the bone conduction thresholds at 1000 and 4000 Hz, while the audiogram for attic fixation had a sigmoidal shape . Using tIncudostapedial joint sclerosis may be caused by manipulation of the joint  or chronic inflammation. Although there were no corresponding clinical cases in the present study, we simulated the effects of sclerotic lesions of the incudostapedial joint by increasing the Young’s modulus 10-fold or 100-fold ,I. A chaThen, we examined the effects of ossicular chain discontinuity . FEMs ofn = 2; n = 6; n = 5; n = 4), and all had traumatic causes of incomplete discontinuity, with two cases described in the surgical records as having soft tissue bands at the point of discontinuity. Cases with an up-sloping audiogram (n = 3), and all three cases had malformations. Two of these cases had complete discontinuity of the ossicular chain, one due to sclerosis of the incudostapedial joint and the other due to discontinuity of the posterior limb of stapes. Cases without a clear up-sloping or down-sloping audiogram (n = 6). The majority of these cases (n = 5/6) were malformations, and all were described as having soft tissue at the point of discontinuity. Three of the six non-sloping audiograms exhibited a shoulder at 1000 Hz (ABG at least 10 dB HL lower than the average of the ABGs at the adjacent frequencies). Thus, it is possible that a combination of factors may be responsible for the impairment of sound transmission in patients with middle ear malformations whose audiograms do not show a clear up-slope or down-slope.The audiological findings were highly variable in 13 patients with suspected incudostapedial discontinuity and an intraoperative diagnosis. The patients were divided into the following groups based on the type of incudostapedial joint discontinuity (complete or incomplete) and the pathogenesis: complete discontinuity of the incudostapedial joint due to middle ear malformation n = 2; , incomplWe also explored whether changes in ossicular mass (a 10-fold or 20-fold increase or a 5-fold or 10-fold decrease) would affect the efficiency of sound transmission. Increasing the mass of the incus and malleus in the FEM  resultedFinally, the coexistence of multiple pathologies was considered. The first FEM evaluated the combination of incudostapedial joint discontinuity and sclerosis of the stapes footplate . When scIn this study, we first constructed a FEM of the normal middle ear and validated it against findings published in the literature. Then, we used our FEM to explore the relationship between specific pathologies  and the audiogram, and the results were compared to audiometric data from clinical cases where possible. Our findings demonstrate that the simulated audiometric pattern for each of the diseases modeled by our FEM was broadly consistent with the averaged audiogram obtained from clinical cases. We anticipate that the results of this study will help to develop analytical methods for pure-tone audiometry that will facilitate preoperative estimation of the pathology underlying conductive hearing loss.The validity of the FEM was first assessed through comparisons with previously published data. The results obtained for the present FEM were similar to those reported previously for simulated tympanic membrane displacement  and measThe sclerotic lesions of the ossicles analyzed in this study included fixation of the stapes footplate, fixation of the malleus and incus to the attic wall, and incudostapedial joint adhesion. The simulated audiograms obtained after FEA indicated that all these pathologies were associated with an up-sloping audiogram, and the results were consistent with audiometric data obtained from 31 clinical cases. Additionally, the FEA showed that the shape of the sloping audiogram differed between stapes footplate fixation and attic fixation, and the ABG at 1000 Hz helped to differentiate between these disorders.n = 4/5) as predicted by the FEM, those with incomplete incudostapedial joint discontinuity due to middle ear malformation tended to have a moderate ABG (n = 5/8) without obvious sloping of the audiogram, and those with complete incudostapedial joint discontinuity due to middle ear malformation had an up-sloping audiogram with an ABG of about 60 dB HL at low frequencies and around 40 dB HL at high frequencies (n = 2/2). We consider incomplete discontinuity of the incudostapedial joint due to trauma to represent a single lesion, whereas the ABG changes associated with middle ear malformations may result from multiple lesions. The up-sloping ABG was similar between cases of complete incudostapedial joint discontinuity, and we consider the changes in ABG to result from a mechanism that did not directly involve the ossicles. In addition, we were able to model the effects of changes in ossicular mass and simulate the audiograms for overlapping sclerotic and discontinuous lesions. Schematic representations of the audiograms for each of these conditions are shown in Since complete discontinuity of the ossicular chain could not be simulated by the present FEM, the analysis focused on incomplete discontinuity of the incudostapedial joint. The results showed that the simulated audiogram exhibited a down-sloping ABG and a threshold that increased with the degree of discontinuity. Evaluation of 19 clinical cases with incudostapedial joint discontinuity revealed a variety of audiometric patterns. Patients with incomplete incudostapedial joint discontinuity due to trauma tended to have a down-sloping audiogram  and is approximately 1000 Hz (800–1200 Hz) in normal subjects . The audAn up-sloping audiometric pattern results from an increase in the stiffness component or a decrease in the mass component. Clinically, otosclerosis (fixation of the footplate of stapes) is known to cause an up-sloping audiogram, and an up-slope would also be expected if the stiffness component increased due to attic fixation of the malleus and incus . HoweverCases with complete discontinuity of the incudostapedial joint also had an audiogram with a large up-slope, but the pathology could not be analyzed with our FEM because our simulation required the transmission of mechanical vibrations between the ossicles. The two cases with complete discontinuity had an ABG above 60 dB HL at 500 Hz and very similar audiogram slopes, which may reflect the bone conduction of sound transmitted through the headphones during the air conductivity measurement and the limit of the ABG that could be measured with a standard pure-tone audiometer. Although a conductive threshold is involved in the ABG, there is some debate regarding the factors that underlie its mechanics. The clinical effects of a reduction in ossicular mass, which can arise due to deformities of the ossicles, are not often discussed. The results obtained with our FEM suggest that, if the continuity and rigidity of the ear ossicles are maintained, a decrease in ossicular mass improves the transmission of high-frequency vibrations and leads to an up-sloping audiogram, although the overall impact of lower ossicular mass on the slope of the audiogram is small.Analysis using the FEM showed that a down-sloping audiogram predominated when the stiffness of the incudostapedial joint was reduced and when the mass of the ossicles was increased. It has been reported previously that a down-sloping audiogram is a sign of incomplete discontinuity . The casThe audiograms of patients with incudostapedial joint discontinuity showed wide variation, necessitating separate analyses of each disease type. Traumatic discontinuity presented with a down-sloping audiogram in most cases and, according to the FEM, could be treated as a single condition of incomplete incudostapedial discontinuity in many instances. On the other hand, all cases of middle ear malformation were associated with a non-down-sloping hearing pattern even when incomplete incudostapedial joint discontinuity was present. The audiograms of patients with middle ear malformations generally had a higher ABG than those of traumatic cases with incomplete incudostapedial joint discontinuity, and the reduced efficiency of sound transmission was likely due to a combination of factors.Published reports indicate that malformations have an average ABG of about 40 dB HL , but traOn the other hand, an increase in the mass component can also result in a down-slope, but clinically this could be due to the attachment of granulation tissue, the presence of an effusion due to inflammation or the attachment of a cholesteatoma matrix. In the FEM, the mass of the ossicles needed to be increased by more than 10-fold to obtain a change in the ABG that exceeded 10 dB HL, which would correspond to a mass of more than 400 mg. Although it is not possible to make a direct comparison, we consider the effects of mass changes on hearing to be less than those of stiffness changes.Since middle ear malformations are assumed to be complex pathologies, we used the FEM to evaluate the effects of combination pathologies on the simulated audiogram. Simultaneous modeling of incudostapedial dissection and footplate fixation showed that the ABGs of each pathology were superimposed and that the audiometric pattern was similar to that seen in patients with middle ear malformations. This suggests that evaluation of the audiometric pattern combined with CT-based assessments of ossicular morphology and attic fixation may allow preoperative estimation of the pathology through the use of a FEM.Although there is no known disease in which only the incudostapedial joint hardens, it is conceivable that the stiffness of this joint increases when it is removed and repositioned during surgery. A dip occurred at 1000 Hz in the simulated audiogram when the incudostapedial joint was stiffened  or when In this study, we have used FEM to simulate the audiograms for otosclerosis, middle ear malformation and traumatic injury, which are all causes of conductive hearing loss. The results are important because they demonstrate that specific pathologies are associated with characteristic audiogram features. The present study did not consider misalignment such as ossicular chain dislocation, hence the development of a FEM to evaluate this pathology remains a challenge for the future. Comprehensive modeling of different conditions with varying severities and simulation of the corresponding audiograms would provide further useful insights. Moreover, this information potentially could be used to develop a system that, in future, would help to predict the site and type of a middle ear lesion based on an individual patient’s audiogram. This method might be particularly effective in cases with complex pathologies, although the FEM will need to be modified to take into account additional factors such as tympanic membrane integrity and middle ear effusion.As many cases of conductive hearing loss are not thought to be due to one simple defect , it will be important to accumulate more cases to improve the accuracy of our model. Although we found notable correlations between the audiograms simulated by the FEM and those of actual clinical cases, the inclusion of more cases might help us to build a model that would estimate the underlying pathology more accurately. In addition, the diagnostic accuracy of the FEM might be improved by incorporating data from other auditory tests or imaging techniques and by focusing on the effects of multiple pathologies.


The mental foramen is a known skull anatomical structure located bilaterally on the mandible along the buccal cortical plate. It is located approximately between the roots of premolars in the anteroposterior dimension, and its supero-inferior level on the alveolar height varies in every individual. The position of the mental foramen is very crucial when surgical interventions are planned in the area. An accessory mental foramina can be very well detected in the three-dimensional (3D) imaging modality, especially in 3D volume rendering images. It can still be appreciated in two-dimensional (2D) imaging modalities such as a panoramic; however, at times it can be confused with periapical pathology, especially in cases where caries are present in the teeth. Three-dimensional imaging modality plays a critical role in identifying such anatomical variation, and hence, it is important to evaluate any surgical site in three dimensions prior to surgical intervention. The mental foramen is located bilaterally on the mandible along the buccal cortical plate. It is located approximately between the roots of premolars in the anteroposterior dimension, and its supero-inferior level on the alveolar height varies in each individual -3. The mThe position of the mental foramen is very crucial when surgical interventions are planned in the area. In cases of implant planning, the location of the mental foramen is essential, especially when there is alveolar ridge resorption, which may lead to a superior location of the foramen. In cases where osteotomy is planned in the area, it is very critical to evaluate the position of the foramen to avoid injuries to the neurovasculature within the foramen.An accessory mental foramina can be very well detected in the three-dimensional imaging modality, especially in three-dimensional (3D) volume rendering images. It can be appreciated in two-dimensional (2D) imaging modalities such as a panoramic; however, at times it can be confused with periapical pathology, especially in cases where caries are present in the teeth .In our case report, we present a unique case of a trifurcated mental foramen, which was incidentally detected when evaluating the cone-beam computed tomography (CBCT) scan for implant planning in the area.A CBCT scan of a 76-year-old male patient was sent for a radiographic evaluation for implant planning at the edentulous site 19. The CBCT scan had a limited field of view, extending from teeth 18-20. The CBCT scan was acquired using the Carestream (Canada) CS9600 at a 0.1-mm voxel size resolution.Initial evaluation of the overall anatomy was done using 3D volumetric reconstruction, which showed three mental foramina on the captured section of the left body of the mandible Figure . The CBCAll three foramina were located apically to the root of tooth 20 within a few millimeters of each other Figure . The supAdditional 2D radiographs, such as panoramic and periapical radiographs, that were available in the patient’s record were evaluated for comparison; these multiple foramina were not appreciated in the 2D radiographs Figure .Several studies have been published in the literature demonstrating the presence of accessory mental foramina -8. TheseThe presence of an accessory mental foramen is considered rare, with its prevalence in the literature showing a varied presentation; it is reported to be between 5% and 30% -15.Although two-dimensional radiographs play a key role in the initial scanning of the area of interest, they lack the actual perception of proximity as well as true identification of the entity in the area. In our case, the multiple mental foramina on the left side were not visualized in the panoramic radiograph. Since the mental foramen opening may be slanted, it may not be clearly visualized due to the superimposition of normal bony trabeculations or distortion of structures due to technique errors . CBCT imThe risk of injury to the neurovasculature in the mental foramen may not just be associated with surgical procedures but also with endodontic treatment in the area -18. A CBIn our case report, the presence of three mental foramina could have complicated the implant surgery if they were not correctly identified. The proximity of these foramina to the implant site played a critical role in the treatment planning, especially in selecting the size and the angulation of the implant placement.Three-dimensional imaging modalities play a critical role in identifying such anatomical variation. Optimal imaging and proper identification of this anatomical variation will provide the correct diagnosis of accessory mental foramina and prevent improper patient care. In order to avoid any complications of regional paresthesia and bleeding, it is crucial to obtain and examine a CBCT scan for accessory foramina during implant placement, apical surgery, or orthognathic surgery in that region.


PSM transfer caps showed higher error frequency in almost all measurements. Only two measurements had a larger error in the analysis models made with Leone transfer caps. The Mann–Whitney U-test found a significant difference between the error levels of TADs found in the analysis models created with PSM transfer caps. Leone transfer caps showed greater reliability in TADs positional information transmission.The aim of this study was to compare the positional information transfer accuracy of palatal temporary anchorage devices (TADs) of two different brands of transfer caps: PSM and Leone. Thirty plaster casts of maxillary dental arches were chosen for master models. A couple of Leone TADs were inserted in each master model. For each master model, two analysis models were created: using two transfer caps, Leone and PSM, the impressions were taken, the analogues were connected on the transfer caps, and the casts were poured. Using digital methods and equipment, such as a 3D scanner, a 3D analysis and a comparison of the accuracy of the two transfer caps in transferring the positional information of the TADs was then made. The data obtained were anal The need to precisely transfer any type of intraoral information to laboratory technicians has always been the most important aspect in every branch of dental clinical practices, and as such, it has been pushing the research ahead in these fields . CustomiThe use of palatal TADs is gaining ground in orthodontics. Adding a skeletal support to a dental anchorage or creating a fully skeletal one is often needed to carry out expansion in adult patients, distalizations, or other movements, which can be too complex to be managed exclusively with dental anchorages ,6,7. DigIf TADs are placed free-hand, according to precise criteria regarding the palatal anatomy , it willIn the orthodontic field, several manufacturers propose their own systems for manufacturing TADs. It sometimes happens that some components of kits from different manufacturers are interchangeable. This came in particularly handy during the first two years of the recent SARS-CoV-2 pandemic period due to a general shortage of materials from various suppliers . This shyzing data obtained using scan bodies to avoid any interference and positional changes, the authors have analyzed the positions of TADs in the final models in order to obtain information about the predictability of these systems. The null hypothesis was that both PSM and Leone transfer caps had the same level of accuracy in TADs positional information transmission.The aim of our study was to see whether this interchangeability could lead to a decrease in transfer accuracy, and investigate which of the above-mentioned two analog transfer caps is more accurate for transferring Leone TADs positional information. Through digital processes, analThe entire study was performed using materials that are normally used in dental offices to simulate the conditions of daily clinical practice.The planning of a skeletal anchorage for maxillary expansion was simulated. Thirty plaster casts of maxillary dental arch were selected from the patient archive of the university dental clinic. The inclusion criterion was good identification of palatal anatomy on the models. The thirty selected models have been catalogued as master models and referred to as codes from 1M00 to 1M029.Two Leone TADs of 2 mm diameter and 9 mm length were inserted in each master model. The TADs have been placed in the anterior paramedian region, at a 4–5 mm distance from the palatal midline, between the second and third palatal rugae. This is usually considered the most appropriate anatomical position for this type of procedures [From each master model, two analysis models were reproduced: one using the Leone transfer cap and, the other using the PSM transfer cap. The Leone transfer caps were positioned and fixed, using the appropriate screwdriver tool, on the TADs’ heads on the master models, then a polyvinyl siloxane impression using Elite HD Putty and Light  with double-phase two-component technique was taken. A plastic impression tray was used for the impression. The impression tray was previously modified by making a window at the TADs on the palate of the master model so that the transfer caps screwed onto the TADs could be accommodated. After hardening of the impression material, the Leone transfer caps were unscrewed from the TADs and the impression was then removed from the master models. The Leone transfer caps remained included in the impression. A couple of the Leone laboratory analogues for each impression were then connected and screwed onto the Leone transfer caps, and the impressions thus composed were used to realize the first thirty analysis models. A type 4 extra hard resin reinforced dental plaster was used to process this last step. A similar process was made using the PSM transfer caps to obtain the other thirty analysis models. The PSM transfer caps, due to their clip-on mechanism, remained directly embedded in the impression material without needing to modify the impression tray or unscrew the caps before removing of the impression. This was simply necessary when inserting the Leone laboratory analogues into the impression at the PSM transfer coping holes in order to be ready to realize the second cast. At the end of the whole process, to distinguish the two sets of analysis models, the letters L and P were added before their respective names thus naming from L-1M00 to L-1M29 for the analysis models made with Leone transfer caps and from P-1M00 to P-1M29 for the analysis models made with PSM transfer caps.The Leone TADs and the two transfer caps, Leone and PSM, used in this study are shown in At the end of the preparation process described above, the thirty master models and their respective analysis models containing the laboratory analogues were sent to the 3D Leone department  where the following steps took place: Digitization of the modelsLeone scan bodies for TADs were screwed onto the emerging head of the TADs and TAD analogues.Models were digitally scanned using a MDS-500 dental scanner and MAESTRO 3D dental scan software  .Each digital master model was superimposed with its respective digital analysis models using some teeth and palatine rugae as reference points . In thisGeometry alignmentFrom the Leone digital library, stereolithography files (STLs) of the scan body and TAD were selected and then coupled together using MAESTRO 3D software (version 5).A coupled scan body and TAD unit were matched with each scan body of every set of models previously embedded as single reference systems using MAESTRO 3D software .Setting the measurement methodTo define the position of the TADs in the area, their axis have been outlined and the angle between their axis and the reference planes were measured and compared . The ide4.MeasurementsFor all TADs of the master models and their analysis models, the angles were measured and the difference between the measurements was calculated . The dis_xy, Angle_yz, Disp_x, Disp_y, Disp_z. To differentiate the parameters of the right and left TADs, dx and sx indications, respectively, have been added to the previously listed terms. The values for the error parameters described above were collected for all sixty analysis models (thirty for those made with Leone transfer caps and thirty for those made with PSM transfer caps).The errors, in terms of angles and displacements, that occurred on different planes and in different spatial directions were listed as AngleThe error values of the two transfer caps have all been reported as positive values because the point was to record the absolute deviation of each TAD from its reference sample. We wanted to compare error values produced by the transfer caps of the two different manufacturers, therefore the data were statistically analysed using Mann–Whitney U-test at a significance level of α = 0.05. The statistical analysis was performed using IBM SPSS Statistics software, version 28.0 .yz-plane and the deviation in the x-axis direction regarding the left TADs. For the latter two measurements, the frequency of error is greater in the analysis models made with Leone transfer caps, with 31.83 in Angle_sx_yz and 33.60 in Disp_sx_x.The mean ranks related to the error levels produced by the two transfer caps in terms of angles and displacements that have occurred on different planes and in different spatial directions are shown in yz-plane and the deviation in the x-axis direction regarding the left TADs. For the latter two measurements, the Mann–Whitney U-test did not find significant differences between error levels of the TADs in the two set of analysis model.According to the data shown in As previously shown in the results, statistical significance exists for measurements whose frequency of error is greater in the analysis models made with PSM transfer caps than for measurements whose frequency of error is greater in the analysis models realized with Leone transfer caps. This suggests that PSM transfer caps have a lower level of accuracy in transferring TAD position information than Leone transfer caps. This could lead to a few problems, mainly related to the difficulty of coupling the appliance during placement in the patient’s mouth, and to potential instability of the appliance in the long term ,20.The authors performed the experiment in such a way as to reduce the risk of introducing inaccuracies and errors of various kinds as much as possible. The manufacturer’s directions were strictly followed for all materials used. In addition, impressions were taken with the double-phase two-component technique which, as described in the literature , yields Regarding these insights, given the paucity of studies in the orthodontic field, we are forced to examine the implantology literature field. Several studies have attempted to compare positional information transfers performed using transfer caps with a screw attachment method versus those with a clip-on mechanism ,22,23. TIn the context of our experiment, we should point out that PSM transfer caps showed some difficulties during coupling to the TADs on some of the master models because of the size of the head of the transfer caps. This problem has been highlighted when PSM transfer caps were used in models with a contracted palate, where a transfer cap on one side bumps against the contralateral, not allowing a complete insertion to be achieved. It is important to specify that this problem is dependent on the head size of the PSM’s transfer caps and not on the coupling with Leone’s TADs, as it can also occur during coupling with the PSM’s TADs.The use of a plaster model for making master models may have posed a risk for the potential instability of Leone TADs following their insertion and during subsequent phases of the study. However, this option represented the easiest way to perform an in vitro study.The Leone transfer caps, which are less bulky and are screwed, guarantee a greater accuracy in the TADs positional information transmission even if their management is slightly more difficult due to the need of modifying the tray before taking the impression and of unscrewing to allow the impression removal. The PSM transfer caps, thanks to their clip-on mechanism, do not require any special maneuvers when taking the impression, but due to an imperfect fit, they can influence the accuracy in the positional information transmission of the TADs. Furthermore, due to their larger rectangular head, in those clinical conditions where there is a significant maxilla transverse contraction, they may bump each other, and thus their insertion could be more difficult, making them even less secure.


For positioning tasks of mobile robots in indoor environments, the emerging positioning technique based on visual inertial odometry (VIO) is heavily influenced by light and suffers from cumulative errors, which cannot meet the requirements of long-term navigation and positioning. In contrast, positioning techniques that rely on indoor signal sources such as 5G and geomagnetism can provide drift-free global positioning results, but their overall positioning accuracy is low. In order to obtain higher precision and more reliable positioning, this paper proposes a fused 5G/geomagnetism/VIO indoor localization method. Firstly, the error back propagation neural network (BPNN) model is used to fuse 5G and geomagnetic signals to obtain more reliable global positioning results; secondly, the conversion relationship from VIO local positioning results to the global coordinate system is established through the least squares principle; and finally, a fused 5G/geomagnetism/VIO localization system based on the error state extended Kalman filter (ES-EKF) is constructed. The experimental results show that the 5G/geomagnetism fusion localization method overcomes the problem of low accuracy of single sensor localization and can provide more accurate global localization results. Additionally, after fusing the local and global positioning results, the average positioning error of the mobile robot in the two scenarios is 0.61 m and 0.72 m. Compared with the VINS-mono algorithm, our approach improves the average positioning accuracy in indoor environments by 69.0% and 67.2%, respectively. With the development of science and technology, mobile robots have been introduced and are widely used in areas such as indoor assistance and environmental awareness. In outdoor areas, the global navigation satellite system (GNSS) can provide an accurate and reliable real-time positioning signal source for robots, meeting the location service needs in most scenarios. However, in indoor environments, GNSS signals are obscured by walls and cannot provide location information to the robot, which requires the use of other sensors to achieve positioning.In recent years, with the development of computer vision technology, simultaneous localization and mapping (SLAM) based in cameras has been developed rapidly, where visual inertial odometry (VIO) uses measurements from vision sensors and inertial measurement units (IMU) to determine the relative motion of a carrier ,2. The cCompared to the VIO local positioning technique, Wi-Fi positioning , the fifDue to the complex indoor environment, any single global positioning signal source will have limitations and low position accuracy. For example, geomagnetic matching uses geomagnetic sequences as fingerprint features, and considering the impact of robot speed variation on time sequences, the dynamic time warping (DTW) algorithm is usually applied to match positioning , but theThe main contributions of this paper are as follows:(a) An error back propagation neural network (BPNN)-based 5G/geomagnetic fusion localization method is proposed, which can provide reliable global localization results in indoor environments;(b) Based on the least squares principle, we solve the transformation parameters of the VIO local positioning results to the global coordinate system, which enables the VIO to output global positioning results consistently;(c) We fuse the global positioning results of 5G/geomagnetic with the local positioning results of VIO by means of the error state extended Kalman filter (ES-EKF) to obtain more stable combined positioning results;(d) Finally, we build an experimental platform based on existing 5G devices, magnetometers and cameras, and demonstrate the reliability and stability of the fusion method under different scenarios.The rest of the paper is organized as follows: With the development of science and technology, mobile intelligent terminals can provide a variety of service modes for people indoors, and the prerequisite for intelligent terminals to provide services is the need to obtain real-time and accurate location information about themselves . ResearcIn recent years, with the research on monocular visual odometry, many classical frameworks have been born, such as LSD-SLAM , ORB-SLATwo key issues in practical applications of VIO are the alignment of local position estimates to the global coordinate system and the reduction in cumulative positioning errors. He  proposedWith the development of indoor positioning technology, an indoor positioning method based on location fingerprint has received wide attention. This method regards the unique feature information of each coordinate point as a fingerprint and achieves the positioning effect by matching the feature information of the point to be measured with the data of the fingerprint library. The most commonly used feature information includes magnetic field strength, received signal strength (RSS) of wireless signal, CSI, etc.  proposedDue to the single feature information, the localization based on geomagnetic matching is prone to mismatching in large-area scenarios, and researchers usually fuse other sensors to achieve indoor global localization. Pan  proposedOur method consists of four parts, the first part is pre-processing of 5G and geomagnetic signals, the second part is a global localization method based on 5G/geomagnetism fusion, the third part is VIO local position estimation and coordinate conversion, and the final part is global position estimation based on ES-EKF.In the positioning based on 5G NR, CSI generally refers to the channel state information obtained by demodulation at the receiving terminal of the 5G signal, which mainly includes the signal amplitude, phase and time delay. As the information on multipath impact, signal propagation time and phase change are different at different locations, but remain relatively stable over time at the same location, there is a certain mapping relationship between location and CSI. As can be seen from When If expressed in decibels (dB), thenreceiver . Due to CSI data , which cAssuming that the magnetometer measures the magnetic field strength in each of the three axes as Since Assuming that the magnetic field strength component measured by the magnetometer in its own carrier coordinate system for the three axes is The BPNN is a feedforward neural network trained according to the error back propagation algorithm, which has a strong nonlinear mapping capability and can meet the requirements of nonlinear mapping between CSI amplitude information, geomagnetic intensity information and real coordinates . The leaThe BPNN consists of an input layer, a hidden layer and an output layer, of which the input layer is responsible for receiving the 5G and geomagnetic information, the hidden layer is responsible for processing the received signal information and establishing a non-linear mapping relationship between the received signal and the coordinates, and the output layer is responsible for outputting the estimated location coordinates. When the input layer receives the 5G and geomagnetic data, it is passed to the hidden layer. The hidden layer will weight and non-linearly transform the data from each neuron in the input layer and pass it to the output layer by forward propagation, and the output layer will output the received results to the outside world. When the output does not match or differs significantly from the desired output, the weights and bias terms of the individual neurons are corrected by back propagation until the threshold of error or the maximum number of iterations is reached. When the network learning training is complete, the 5G and geomagnetic data of the point to be measured is input, and the localization results can be output by forward propagation.Suppose the input vector of a neuron is Then, the state output of this neuron isFor local position estimation, we used existing VIO algorithms. There are many excellent VIO algorithms such as VINS-mono , ORB-SLAThe conversion of the local position estimate of VIO to the global coordinate system is shown in Assume that the output of a position is Each pair of point coordinates can be calculated from the above equation to obtain a set of corresponding Treating The above equation is translated into matrix form asThe rotation and translation matrices can be solved by using the least squares principle, and the local position estimate is then converted to a global position estimate by Equation (15).The ES-EKF-based fusion localization process is shown in In the fused localization algorithm, we use the planar coordinate system obtained by the 5G/geomagnetic fingerprint library as the global coordinate system, the position and velocity of the carrier as the state vector of the system, then the state vector at the Since the state vector of the combined system includes only the position and velocity of the carrier, we treat the acceleration as the random noise of the system. For the combined system, we take the difference between the VIO and the 5G/geomagnetism output position estimate as the observation vector, In order to verify the indoor positioning performance of the proposed fusion positioning algorithm, we first evaluated the global positioning method with 5G and geomagnetism fusion, and then conducted field tests under two different scenarios. The experimental equipment was built as shown in We first used continuous path acquisition to collect 5G and geomagnetic information in the experimental area, and then interpolated the positions on both sides of the path by kriging interpolation, to make a uniform distribution of the location fingerprint library points with an interpolated resolution of 0.5 m × 0.5 m. After the location fingerprint library was established, we used a pre-built unmanned vehicle carrier platform to move along the established trajectory, with three sensor output measurements delivered simultaneously to the same computer, which were then solved in real time using our proposed fusion localization algorithm. The T265 camera was responsible for outputting image and IMU information at 50 Hz and 200 Hz, respectively, the magnetometer was responsible for outputting geomagnetic 3D vector information at 50 Hz and the 5G device was responsible for outputting CSI data, which was also at 50 Hz. In the VIO localization process, the IMU output was pre-integrated and then fused with the image data, its final output of position estimation data was also at 50 Hz. During data collection, 5G collects CSI for the single base station case, containing a total of 60 subcarrier amplitudes, which were localized as fingerprint information after subcarrier aggregation based on the free-space model in We first tested the localization effect of the 5G and geomagnetism fusion global localization method using some points in a conference room. The cumulative distribution function (CDF) of errors for the 5G localization, geomagnetic matching localization and 5G and geomagnetism fusion localization methods are given in As can be seen from As the VIO localization method is susceptible to lighting problems and is also prone to cumulative errors, we first tested the localization effect of our localization algorithm in a poorly lit scene. We tested it at night in a conference room; the experimental area was about 58 square meters, and only one row of lights near the x-direction was kept on during the experiment, the rest of the lights were turned off. We drove the unmanned vehicle from point  in a clockwise direction. As can be seen from the figure, the VIO trajectories generally perform poorly and have large deviations from the true trajectories, which may be caused by the lack of indoor lighting. Whereas the output trajectory is relatively close to the true trajectory on the left-hand side, it gradually deviates from the true trajectory on the remaining three sides, mainly due to the cumulative errors that exist over time. In contrast, our proposed fusion localization algorithm largely suppresses the drift in position estimation, and after ES-EKF filtering, its trajectory output is smoother and closer to the true trajectory. However, after fusion, its predicted trajectory on the left side is somewhat far from the real trajectory, while the remaining three sides are significantly improved. This may be due to the larger fusion positioning error of 5G and geomagnetic relative to VIO, which caused a decrease in the positioning accuracy of the left side after fusion. Overall, its positioning trajectory has been greatly improved. The CDF plots of the two methods are shown in The localization error distribution of VIO is more diffuse, mainly concentrated in the range of 0–1 m and 3–4 m, which is caused by its large error on the x-axis compared with 2, a larger area than the conference room; however, the experiment was conducted in daylight and the light was brighter in experiment (A) than in experiment (B). Additionally, to verify the effect of the driving route on the results of the experiment, during the experiment we drove the unmanned vehicle still from the point , but in a counterclockwise direction for one revolution. Additionally, a comparison of the trajectories estimated by the two algorithms with the real trajectories is shown in Experiment (B) verified the effectiveness of our algorithm for localization in a small area in a dark night-time environment. To further validate the localization performance of the fusion localization algorithm, we tested it in a corridor. The experimental scene is shown in The output trajectory was closer to the real trajectory in experiment (A) than experiment (B), because the experiment was carried out during the day with good light, which enabled more feature points to be extracted. It can be seen that the brightness of the light had a greater impact on the position estimation of the VIO, and therefore this experiment is more reflective of the real VIO position estimation because of the better light. The position estimation of the VIO is better in the early stage, and as time goes on, its cumulative error becomes progressively larger and gradually moves away from the true trajectory in the end, i.e., the situation is worse on the left-hand side and relatively better on the remaining three sides. The trajectory of the fused positioning algorithm is close to the real trajectory on the whole. The VIO localization error in this experiment does not show a sudden change in error compared to experiment (B), but rather a smoother gradual increase, but the maximum localization error reached a value of about 4 m due to the large area. It can be seen that the accumulation of errors in the large area is an urgent problem for VIO position estimation, irrespective of the problem of light and darkness. With fusion, the overall localization errors of our algorithm were all within 2 m, with most of the points having a localization error within 1 m. VIO localization techniques have high accuracy over short periods of time, but are subject to cumulative errors and cannot fulfill the positioning needs of indoor robots for long periods of time. Global localization techniques that rely on indoor signal sources do not suffer from cumulative errors, but the overall localization accuracy is low and cannot provide reliable global localization results. In this paper, the 5G and geomagnetic signals are first fused for global localization, and then the global localization results are fused with the localization results by the ES-EKF algorithm. Through experiments with unmanned vehicle carriers, the following conclusions can be drawn:(a) The BP neural network-based fusion positioning of 5G and geomagnetic signals reduces the large positioning errors from a single source. After fusion, the average positioning error is 0.49 m, which is 0.27% and 0.17% better than the single sensor positioning methods of geomagnetic and 5G signals, respectively;(b) Loosely combining the local localization results of VIO with the global localization results of 5G and geomagnetic, not only solves the problem of VIO not being able to provide global localization results, but also reduces the positioning error of VIO. After loosely coupling, the average localization error in the two scenarios is 0.61 m and 0.72 m, which is a 69.0% and 67.2% improvement, respectively, on the currently popular VINS-Mono algorithm with a single VIO. This demonstrates that the algorithm in this paper can improve the accuracy and robustness of indoor positioning.Considering that the filter-based method proposed in this paper can provide real-time localization results, but still lacks in accuracy compared to the optimization-based method, in future work we will consider how to combine both real-time and accuracy of localization. In addition, given that the localization work in this paper was mainly carried out on a two-dimensional plane, with the future development of space technology, the 3D position information of mobile robots has also become more important, so in future research, we will consider using UAVs as platforms to achieve three-dimensional localization of robots.


The modern approach to quality control (QC) in medical laboratories implies the development of a risk-based control plan. This paper aims to develop a risk-based QC plan for a laboratory with a small daily testing volume and to integrate the already optimized moving average (MA) control procedures into this plan.A multistage bracketed QC plan for ten clinical chemistry analytes was made using a Westgard QC frequency calculator. Previously, MA procedures were optimized by the bias detection simulation method.Aspartate aminotransferase, HDL-cholesterol and potassium had patient-risk sigma metrics greater than 6, albumin and cholesterol greater than 5, creatinine, chlorides, calcium and total proteins between 4 and 5, and sodium less than 4. Based on the calculated run sizes and characteristics of optimized MA procedures, for 6 tests, it was possible to replace the monitoring QC procedure with an MA procedure. For the remaining 4 tests, it was necessary to keep the monitoring QC procedure and introduce MA control for added security.This study showed that even in a laboratory with a small volume of daily testing, it is possible to make a risk-based QC plan and integrate MA control procedures into that plan. Traditional quality control of analytical work is performed by testing commercially available control materials at certain time intervals. Statistical rules are then applied to the obtained results of control measurements to check their acceptability  and the external and internal quality control at the Department of laboratory diagnostics, Railway Healthcare Institute, for the period July 2019 to June 2020. The laboratory provides services to a general adult population at the primary level of healthcare, with an average annual number of about 400,000 tests. The following 10 analytes were included in the study: albumin, aspartate aminotransferase (AST), creatinine, calcium, chloride, cholesterol, HDL (high-density lipoprotein)-cholesterol, potassium, sodium, and total proteins. These analytes were chosen because the laboratory already has optimized MA procedures implemented in the LIS . All tests were performed on the Architect c16000 clinical chemistry analyser  with the original reagents. Consent for the use of data from the LIS in this study was obtained from the Ethical Committee of the Railway Healthcare Institute.For all 10 tested analytes, sigma metrics were calculated according to the formula: Sigma = (TEa - Bias) / CV, where all values in the formula are expressed in %.The total allowable error (TEa) value was taken from the Clinical Laboratory Improvement Amendments (CLIA) data (The coefficient of variation (CV) was calculated based on internal QC (IQC) data from the clinical chemistry analyser for the period of 6 consecutive months. One lot of commercially available control material  with 3 levels of value was used.The bias value for each analyte was calculated based on the results of a monthly external QC program the laboratory participates in . From the external control results for 12 consecutive months, those values were selected that correspond to the target values of the analyte in the levels of the material used for IQC. For each of the three levels of internal control, 3 external control samples were found in corresponding concentrations. For each of these groups of three samples, the arithmetic mean of the bias obtained in external control was calculated, and this value was considered the bias for the corresponding analyte concentration level.A multistage bracketed risk-based QC plan was developed for each examined analyte using the Westgard QC Frequency or Run Size Calculator  procedures if using 3 levels of control material are presented in per day) and the work organization (one-shift work without urgent service or emergency requests), we chose a reporting interval equal to the daily number of tests. Following guidelines from the literature, we then made a start-up QC plan, which would be implemented at the beginning of each working day before the analysis of patient samples, and a monitoring QC plan, which would be implemented periodically during working day   and the desired reporting interval (size of the series of patient samples after which the results are issued to users). Due to the small daily number of tests in our laboratory  was ≤ 0.05.i.e., the key parameter for optimization was the ability of an MA procedure to detect bias of TEa size within the total number of daily tests performed by the laboratory  , we believe that MA provides additional security between two SQC events. In case a bias occurs in the analytical system, it will be signalled by an MA alarm, allowing us to perform the SQC without waiting for the interval provided by the plan to expire and thus to confirm or deny the existence of a problem requiring corrective action. The ability of the sodium MA procedure to detect clinically significant bias in one-third of the daily number of results prompted us to select the same SQC monitoring procedure for all tests that were to be performed, despite the calculated run size for sodium being discretely smaller than the maximum daily number of tests.Regarding the implementation of PBRTQC into a traditional SQC plan, we agree with other authors that, though alone it is not enough, PBRTQC certainly deserves a place in routine laboratory practice, in addition to traditional control (i.e., many times greater than their daily number. Based on the characteristics of the MA procedure, we acted differently with chloride and creatinine. Since the MA procedure for chloride reveals a clinically significant bias in one-third of the daily number of tests, we classified it into tests in which MA is a replacement for the SQC monitor. In the case of creatinine, we decided to keep the monitoring SQC procedure because the existing MA procedure does not guarantee the detection of a positive critical bias within the daily test production.When it comes to tests from the medium sigma metrics group, we were more careful than with high sigma metrics tests, even though the run size covered by the start-up rule is 1000 tests, Regardless of the value of the test’s sigma metrics, it should be noted that PBRTQC has the ability to detect both preanalytical and analytical errors; hence, adding this type of procedure to the QC plan can yield multiple benefits (When developing a multistage QC plan, it should be kept in mind that increasing the frequency of QC inevitably increases the laboratory costs. This is particularly problematic for small laboratories where the percentage of controls in the total daily number of tests may become an unacceptable cost, even in the case of tests with good sigma metrics, unlike in laboratories with large testing volumes (One of the key parameters for calculating sigma metric and thus the run size between two QC measurements is the quality requirement of a specific test, expressed as TEa (Regarding the limitations of our study, we have only developed a risk-based QC plan for 10 clinical chemistry analytes but it should be applied to all tests performed by our laboratory. Also, it would be necessary to examine in routine practice how often the MA procedure will detect a problem before the scheduled monitoring SQC procedure.In conclusion, we can say that the study has shown it is possible to make a risk-based QC plan even in a laboratory with a small daily volume of testing, and MA procedures deserve their place in this plan.


Monitoring product temperature during lyophilization is critical, especially during the process development stage, as the final product may be jeopardized if its process temperature exceeds a threshold value. Also, in-situ temperature monitoring of the product gives the capability of creating an optimized closed-loop lyophilization process. While conventional thermocouples can track product temperature, they are invasive, limited to a single-point measurement, and can significantly alter the freezing and drying behavior of the product in the monitored vial. This work has developed a new methodology that combines non-invasive temperature monitoring and comprehensive modeling. It allows the accurate reconstruction of the complete temperature profile of the product inside the vial during the lyophilization process. The proposed methodology is experimentally validated by combining the sensors’ wirelessly collected data with the advanced multiphysics simulations. The flexible wireless multi-point temperature sensing probe is produced using micro-manufacturing techniques and attached outside the vial, allowing for accurate extraction of the product temperature. As reported in1, about 50% of new injectable/infusible drugs approved by the Food and Drug Administration (FDA) in recent years were manufactured in a sterile powder form requiring lyophilizaiton or a similar drying technology.Lyophilization, or freeze-drying, is a commonly used and well-established process that is developed to preserve the original structure of heat-sensitive biological and pharmaceutical products  for more manageable long-term storage and shipment. Freeze-drying involves ice removal from a frozen product at low pressure through a sublimation process. According to the “Markets and Markets” report  inside the solution to be freeze-dried is the standard industry practice today11. A simplified thermal model is used for the deconvolution of the vial wall temperature to the product temperature. In this work, the deconvolution parameters used in the process were identified using the inner temperature measured by a conventional thermocouple; however, such modeling can be biased by the thermocouple presence12. Our previous work13 proposed a wireless solution based on low-power sensing electronics to measure product temperature. This approach resolves the TC-induced heating concern while allowing for direct product measurement. However, the sensing is invasive and may interfere with the freeze-drying behavior.More advanced approaches have been proposed to monitor the product temperature of individual vials during the freeze-drying process. A non-invasive temperature monitoring method with thin-film thermocouples (TFTCs) printed on the outside wall was proposed by Oddone et al.14 which can be fused in the vial bottom and used non-invasively. Another solution is a sputtered thermocouple method15 which includes arrays of sensors. It is worth mentioning the temperature remote interrogation system (TEMPRIS)16 which works remotely receiving the energy from the electromagnetic field. One of the latest works of Lietta17 describe the use of infrared thermography for monitoring a vial freeze-drying process. The main drawbacks of OFSs are the complexity of manipulations needed to fuse the glass fiber in the vial’s bottom and the impossibility of automatic loading, whereas the sputtered thermocouple also involves a complex manufacturing procedure. The infrared thermography method requires the setup of an IR thermal camera inside the freeze-dryer and can only measure the temperature of the vials standing in front of it. The main disadvantage of TEMPRIS is a large size of an invasive probe. Finally, Barresi18 described the “smart vial” concept using thermocouple readings from the side of the vial to reconstruct the temperature inside the vial.There are several non-invasive solutions for temperature measurements reported in the literature. One of them is the optical fiber sensors (OFSs)19 and Millman20 have been investigating the freeze-drying process in a vial and developed one-dimensional numerical models. Later, Mascarencas21 and Sheehan22 developed finite element and multidimensional models for primary and secondary drying modeling. In 2011, Koganti23 used modeling to build the design space of the primary drying stage of freeze-drying process. Shivkumar24 developed a primary drying simulation, design space generation, and process optimization tool. In one of the recent works, Ravnik et al. proposed a 1D numerical model to simulate the heat transfer and vapor diffusion process in a vial25 with accurate capturing of temperature levels inside of the drying material. The model demonstrated a reasonably good agreement with experimental results.The modeling of the freeze-drying process in a vial has been developing over the last three decades. PikalThis article presents a new virtual thermocouple technology that allows for a non-invasive, fully wireless, robust measurement approach that overcomes the aforementioned main limitations. This technology comprises three main parts: (a) the flexible non-invasive multi-point sensing probes that are externally attached to the vials, (b) the low-power wireless electronics that read and transmit data wirelessly, and (c) the 2D numerical model that translates the temperature profile measured from the vial wall to the actual product temperature in any point during the primary drying process. This study demonstrates that the proposed method can effectively be used for non-invasive real-time monitoring of the drying dynamics and product temperature during the freeze-drying process.The non-invasive wireless tracking system has been designed to monitor a freeze-drying process across the entire batch with near-zero interaction with the actual product. We are achieving it by monitoring temperature at various locations and tracking the sublimation front of the lyophilization process. This method relies on (a) attaching flexible temperature sensing probes to the outside of the vial and (b) using multiphysics simulation to extract the temperature of the product inside the vial.15 The wireless and flexible film design allows for use of the sensing element multiple times with different vial sizes and without restricting industrial automatic loading practices. In addition, multiple NTC (Negative Temperature Coefficient) thermistors mounted to the flexible substrate allow measuring temperature at various heights across the vial. The end-user can revise the design accordingly to the vial dimensions used. In this paper, we include five sensing elements in each sensing probe with the bottom element placed at the base of the vial. The distance between two adjacent sensing probes is 3.05 mm.A flexible multi-point sensing probe is designed and fabricated using photosensitive lithography and chemical etching. The manufactured device is capable of extracting information concerning the temperature of the product during the lyophilization process. Figure Figure entclass1pt{minimaR) dependence versus temperature (T). Due to having a large negative slope, a small temperature change will cause a substantial change in electrical resistance at a lower temperature. The disadvantage of such a thermistor is its nonlinear characteristic. Consequently, each thermistor has to be calibrated to ensure measurement accuracy. The Steinhart–Hart (S–H) equation is the most commonly used model to describe the nonlinear characteristic of the thermistor, as shown below.T is the temperature in degrees Kelvin, ln (R) is the natural logarithm of the measured resistance of the thermistor, and A, B, and C are constants. To obtain the values of these constants, each thermistor is used at three different temperatures: 20 The NTC thermistor is a small footprint . The temperature sensing thermistors are connected to a 31 has shown the different methods of electronic sterilization for similar applications.Figure 32 software. The model allows obtaining the temperature distribution on the vial surface and inside the vial (product temperature). The simulation results are validated against the actual measurements and further investigated.To understand the temperature profile measured by the multi-point flexible sensing elements, we create a numerical model for the primary drying stage of the solution in a vial using the COMSOL multiphysicsIn the proposed model, we numerically solve the transient (time-domain) heat and mass transfer problem during the primary drying stage of the freeze-drying process for the product in a glass vial. The variation of the product and vial temperatures and the position of the sublimation front is predicted. The geometry and the boundary conditions for the 2D axisymmetric problem statement are shown in Fig. 33):The following modules were used in COMSOL simulations: “Heat Transfer in Porous Media”, “Darcy’s Law” and “Deformed Geometry”. Several heat-transfer mechanisms are accounted for in this model: convective heat fluxes from ambient, heat exchange between vial, dried/frozen product, and shelf. The heat transfer equations for the ice region without convection and for the dried region with convection are solved. The mass transfer is resolved using Darcy’s law and the vapor density is calculated with the ideal gas law. The heat exchange with the surrounding air and the shelf is represented by the heat transfer coefficients. The dried and frozen regions are assumed to be homogeneous, and the presence of the inert gas during the primary drying process is neglected. The chamber pressure is set at the top of the product. The main parameters’ values used in the simulations are listed in Tables The coupled heat and mass balances are solved on the moving mesh interface and lead to the Stefan condition to obtain the interface velocity:The simplified vial geometry used in the COMSOL simulation is shown in Fig. Freeze-drying runs were performed in a laboratory-scale freeze-dryer  located at the LyoHub research lab, Purdue University, as shown in Fig. Three sets of freeze-drying experiments are performed with this setup to evaluate the flexible temperature sensor performance. Each set focuses on exploring a different scenario, as described in the following paragraphs. In addition, experiments in each set are repeated at least three times to provide reliable data. Predefined freeze-drying recipes Table  are usedhttps://www.sio2ms.com/ ). We also insert conventional thermocouples (TCs) at the bottom-center location in each vial type to measure the product temperature. A Thermal IR camera (FLIR Lepton 3.5) is used to monitor the freezing behavior of the product.The first set of experiments Fig. a focusesThe second set of experiments Fig. b focusesIn the third set of experiments Fig. c, four vFigure Thermal image #1 shows the moment right before nucleation occurs in both vials. As shown in Fig. In addition, the post-nucleation temperature profiles of the two vials are different as well. As the sensing elements indicate on point #4, the glass vial is cooled from the bottom. Temperature is gradually increasing from the bottom to the top of the vial. On the other hand, such a cooling profile was not observed in the case of the plastic vial. The product seems to freeze uniformly inside the plastic vial. These results show that flexible sensing elements successfully capture the freezing dynamics in both vials.We model the primary drying stage and compare the virtual thermocouple readings with actual experimental data. A whole shelf of 6R vials (403 units) filled with 4 ml 5% mannitol solution is freeze-dried in the REVO Millrock lyophilizer. The chamber pressure is set to 60 mTorr and shelf temperature to 20 mentclasspt{minima34. The primary drying ends as the Pirani reading converges to capacitance manometer measurement. All temperature sensing elements showed perfect agreement in the temperature readings profile with the data obtained from the thermocouples. Interestingly, both multi-point temperature sensing elements indicated an early increase in temperature close to the end of primary drying relative to conventional thermocouple data identifying the vials’ walls heating.Figure 35 where the experimentally measured39 values and the data from The International Association for the Properties of Water and Steam Formulation40 were utilized for water vapor viscosity in the range of The performance of the virtual thermocouple was validated using data from the freeze-drying experiments as mentioned in previous sections. The numerical model was tuned to match the sensing element data during the primary drying stage demonstrated in Fig. The solid lines in Fig. Figures 41 as a function of the dried thickness or cake thickness Figure 19:41 are very close. The product’s resistance is a parameter that can be affected by the freezing protocol, particularly with the temperature of nucleation. Even though the current simulation considers the nonuniform heating of the vial and accounts for product and vial properties, some factors cannot be directly measured and accounted for in the simulation. For example, the relative position of the vials on the shelf can vary due to the loading process or human factor, the variation in shelf heat transfer and pressure distribution within the chamber are also among such factors. In general, in addition to the product temperature match, the shape of the The cake resistance from the current simulation is calculated according toWith the ability to measure the product temperature close to the center of the vial bottom during primary drying, we utilize the power of the virtual thermocouple to investigate the effects of conventional thermocouple heating. Figure The development of optimal lyophilization procedures for different formulations in vials includes experimental tests and computational approaches for measuring product temperature. Tight temperature control is essential in both the freezing and primary drying steps because the freezing and primary drying protocols determine the structure of the dried product (cake). To obtain the uniformly dried product across the batch, one needs to control the temperature during these stages accurately. Notably, ice nucleation during the freezing stage should occur in a tight temperature interval. Most importantly, the product temperature must be kept safely below the collapse temperature during the primary drying stage. Due to the presence of bound water in the product after the primary drying stage, the collapse temperature can be relatively low. Moreover, the critical process parameters should be controlled accordingly to optimize the process and reduce the primary stage duration. Along with the chamber pressure, shelf temperature is one of such parameters which defines the design space for the primary drying stage of the freeze-drying process. Traditionally, the shelf temperature depends on the temperature of heat transfer fluid  inside the shelves, which is tracked by the control system and is set to follow the pre-set profile. However, the heat transfer control obtained by the control and manipulation of the shelf temperature is relatively slow, partly because of the thermal inertia of the system, due to which shelf heating and cooling may induce a considerable lag in the response of the product temperature. Alternatively, the chamber pressure of the dryer can be controlled and manipulated since the heat flux from shelf to product strongly depends on it. However, this approach can be pretty risky because the product temperature practically follows the pressure variations; therefore, changes of a few pascals could easily jeopardize the product quality.Since the critical part of any lyophilization procedure is the primary drying stage, special attention has to be paid to the critical modeling parameters of drying a porous cake-solid ice system. In this work, a new technology, virtual thermocouple, based on the use of flexible multi-point temperature sensor and advanced multi-physics simulation, was proposed and investigated as a means for the monitoring of freezing and drying behavior and product temperature during the freeze-drying process. The developed virtual thermocouple combining the two-dimensional model with the surface sublimation sub-model can be used as a stand-alone, fast, and accurate computational tool to predict lyophilization dynamics. However, it can also be included in a general 3D CFD computational framework as a vital part of the final virtual lyophilizer model. Moreover, the two-dimensional freeze-drying model can be extended into three dimensions and accurately capture the non-uniform vial heating effects such as edge effect and 3D shape of the sublimation front inside the vial. The proposed virtual thermocouple was found to give quantitatively accurate results for drying behavior. In particular, the flexible multi-point sensing elements can give information about the temperature profile on the vial wall. This information, combined with the advanced multi-physics simulation, provides the actual product temperature, position, and shape of the sublimating interface and perfectly matches conventional thermocouple measurement. The proposed virtual thermocouple technology can effectively track the temperature profile within the volume of the solution of an individual vial during the freeze-drying process.Supplementary Information.


Marine plastic pollution is a critical environmental challenge facing policymakers globally. To reduce marine plastic pollution by engaging the people, this study estimated the determinants of waste disposal approach by households, their willingness to participate in road gutters/drainage channels cleanup program and the number of man-days they are willing to contribute. The study used a total of 600 households drawn from 30 enumeration areas. A semi-structured questionnaire was employed in data collection. Means, percentages, multinomial logit model and Heckman selection model were employed in data analysis. The study found that most (67.42 percent) of the households in the coastal city of Lagos engage in illegal waste disposal. Some variables, household size, involvement in previous community cleanup activities, receipt of waste management information, payment of waste management fee, and having a dumpster in a locality, significantly reduce the likelihood of illegal waste disposal. The study also found that most (75.50 percent) of the households were willing to clean up road gutters/drainage channels; however, most (83.20 percent) were only willing to contribute one man-day (eight hours) in a week. Gender and previous participation in voluntary service significantly influenced both households’ willingness to participate and the number of the man-days they are willing to contribute. Women are more likely to participate and contribute man-days to the activity. Education, household size and amount paid as waste management fee significantly reduced the number of man-days households are willing to contribute. In contrast, the provision of information on waste management significantly increased the number of days they are likely to participate. The study recommended providing waste management information and dumpsters to reduce illegal waste disposal, mobilizing citizens, especially women, the less educated and low waste fee-paying households, through well-packaged information about plastic pollution. Marine plastic pollution is one of the major environmental issues threatening aquatic life, and its management is now considered a critical environmental priority . PlasticMarine plastic pollution resulting mainly from land-based sources contributed between 4.8 and 12.7 million tons in 2010 and is expected to double by 2025 if adequate measures are not taken to limit it . Due to The impact of marine plastics pollution on marine life and human livelihoods is enormous. Plastics impact wildlife in the oceans through ingestion, entanglement, bioaccumulation and distortions in the ecosystem integrity . ThroughCountries have applied different policy instruments in order to deal with the problem of marine plastic pollution. Policy instruments have targeted plastic production, consumption and disposal. Policy instruments that have been used include price-based instruments, (e.g. increasing the prices or imposing taxes on plastic products); regulation instruments, (e.g. bans); rights-based instruments, (e.g. waste-based billing); and behavioral instruments (engaging the people), for example, education, information and cleanup campaigns ,13. In ADespite the use of bans and taxes and other policy initiatives in Africa, Sub-Saharan Africa (SSA) accounts for 9 percent of mismanaged plastic waste globally , even asThus, given that regulatory and price based policy instruments are still inefficient in dealing with marine plastic pollution in SSA and many developing countries ,6, especTherefore, to effectively engage people in dealing with marine plastic pollution, there is a need to understand their waste disposal approach, determine their willingness to participate and socioeconomic and other factors that can support people’s engagement. Policy instruments are more effective when the target population’s characteristics are considered in their design than not . AlthougThe rest of the paper is structured as follows: section two is on conceptual framework and literature review, section three focuses on the methodology, section four is result and discussion, and section five concludes.In line with the conceptual framework , plasticPlastics are consumed by households, industries, institutions . Single-use plastic products popularly used in Nigeria include plastic bags, especially polyethene (cellophane), popularly used in wrapping consumables, takeaway food packs, cups, straws, and spoons. However, plastic sachet bags for packaging water, often called "pure water", are the most widespread –42. AftePrevious studies have determined factors that generally influence households’ participation in beach cleanup schemes and waste management.  found thThe study area was Lagos State, Nigeria, a coastal State with 9,013,534 inhabitants in 2006  and an aTo ensure a representative sample of households, household selection involved sampling of households from the Enumeration Areas (EA) used by the National Bureau of Statistics (NBS). EA is a cluster of housing units as delineated by the National Population Commission. A two-stage sampling process was applied in the selection of households for the study. First, we randomly sampled a total of 30 EAs for the study. From each EA, twenty (20) households were randomly sampled, giving a total of 600 households for the study.Data collection involved the administration of a semi-structured questionnaire with tablets using the "Survey Solutions" software . The queBefore actual data collection, we carried out key informant interviews and focus group discussions through which additional information about waste management practices in Lagos and the general perception of the people regarding plastic pollution were obtained. The information obtained helped in updating the questionnaire. The questionnaire was subjected to a pilot study using 30 households selected from three EAs, ten from each. The EAs used for the pilot study were not part of the actual study. The pilot test facilitated the collection of some open-ended questions regarding the people’s opinions on different issues, for example, environmental effects of single-use plastics. The responses to the open-ended questions enabled us to gain insight into the issues and thus helped us provide options regarding those issues in the questionnaire.We first used descriptive statistics to evaluate the respondents’ opinions regarding the waste disposal approach and their perception regarding single-use plastics and their effect on the environment. Secondly, following the conceptual framework, we applied the multinomial logit (MNL) model to estimate the determinants of the waste disposal approach employed by the households to find out the drivers of legal  as against illegal disposal. MNL has the advantage of allowing the analysis of decisions involving three or more categories, thereby enabling one to determine probability choices for different categories ,52. The βj. The model is subject to constraints 0<pij<1 and Where Furthermore, a bivariate sample selection model was applied to estimate households’ willingness to participate in a cleanup of road gutters/drainage channels program and the number of man-days/hours they were willing to participate in a week. The bivariate sample selection model  has bothy2 is observed when y2 has no value when From the model, ε1 and ε2 is zero.Sample selection is confirmed if the correlation between Specifically, we applied the Heckman sample selection model  to estimyj (number of man days or hours a respondent is willing to participate to clean-up road gutters and drainage channels) for observation j is only observed ifThe dependent variable Selection equationWhereβ and α are coefficient of the variable in Eqs (σ (sigma) is the error term in the outcome equation; while Dpr is inverse mills ratio plus the probability of being selected [e in Eqs  and 6)  βk−. According to , a variaRegarding the issue of single-use plastics harming the environment, the majority (92.50 percent) believed that single-use plastics harm the environment. Only 6.00 percent indicated that single-use plastics do not harm the environment, while 1.50percent did not know. This finding is in line with that of , who fouOn how they knew about the environmental problems associated with single-use plastics, the majority (74.42 percent) indicated that they received the knowledge through their personal experiences. At the same time, none got the knowledge through published material. On the most severe environmental problem associated with single-use plastics, the result presented in On the waste disposal approach employed by the households, the result shows that the highest proportion (47.04 percent) of the respondents dispose of waste through informal waste collectors or cart pushers, 32.58percent dispose of waste in bins/dumpsters provided by government or government-appointed private sector participants (PSPs). In addition, 13.41percent dispose of waste in open waste dumps or any space they found around their street/residence, and 6.97 percent burn the wastes they generate. This result shows that most (67.42 percent) of the households in the coastal city of Lagos dispose of the waste they generate through illegal waste disposal means. This finding aligns with  that in Furthermore, the result of the MNL regression showing the coefficients and marginal effect of the determinants of the waste disposal approach used by the households is presented in On the other hand, the result shows that having the perception that single-use plastics should not be banned increases the likelihood of open dumping of waste. This implies that those who said that plastics should not be banned also carry out illegal waste dumping. The marginal effect results show that having the perception that plastics should not be banned increases the likelihood of open dumping of waste by 5 percent. This finding suggests the need to provide information on the dangers of single-use plastics to households to discourage illegal dumping of wastes. Also, although not expected, the result equally shows that participating in voluntary service increases the likelihood of illegal waste disposal, that is, open dumping of waste, use of informal waste collectors and burning of waste. The marginal effects show that participating in voluntary service increases the likelihood of waste disposal through informal waste collectors and cart pushers by 21 percent. The high marginal effect could be because those who participated in voluntary service saw the informal waste collectors as “voluntary people” who filled the space and helped in providing a service that the government did not provide. Besides, research evidence  shows thThe result of the household heads’ willingness to participate in a program for the cleanup drainage channels is presented in The result of the sample selection model of the determinants of the respondents’ willingness to clean up drainage channels and the number of man-days they are willing to contribute is presented in In addition, social capital variables which include, having participated in voluntary service and having ever been involved in community cleanup activities, significantly influenced the willingness of households to participate in the cleanup of drainage channels program. The finding also shows that participating in voluntary service significantly increases both the willingness of a household head to participate and the number of days they are willing to contribute. Given that the variable appeared in both the selection and outcome equation, the result of mean correction shows that participation in voluntary services significantly increases the likelihood of contribution of man-days to the cleanup of road-gutters and drainage channels by four percent . Also, hThe result equally shows that the waste management practice of the households influenced their willingness to participate in the cleanup of drainage channels and the number of man days they are willing to contribute. Specifically, the result shows that paying waste management fees increased significantly the likelihood of a household’s participation in the clean-up of road gutters and drainage channels program to reduce the flow of plastic into the ocean. On the other hand, the number of days the households are willing to contribute reduces with an increase in the amount they pay for waste management. This suggests that a household that pays a waste management fee would be willing to clean up drainage channels to reduce the flow of plastics into the ocean. However, the households that pay higher fees would not contribute many days to the clean-up of road gutters and drainage channels program. This finding is expected as those that pay waste management fees are already committed to waste management and would be willing to participate in waste management activities regarding plastic pollution. However, those that pay more may feel that the money they pay could account for the contribution of days and would not be willing to contribute many days. This finding is in line with that of  that fouThe study estimated the determinants of households’ waste disposal approach, their willingness to participate and the number of man days they are willing to contribute to a clean-up of road gutters and drainage channels program to limit the flow of plastics into the ocean. The study found that most (67.42 percent) of the households in the coastal city of Lagos dispose of the waste they generate illegally. Some variables, namely, household size, having ever been involved in community cleanup activities, receipt of waste management information, payment of waste management fee and having a dumpster in a locality, significantly reduced the likelihood of illegal waste disposal. Also, most (75.50 percent) of the households were willing to clean up road gutters/drainage channels before the onset of rains to reduce the flow of plastics into the oceans. However, the majority (83.20 percent) were only willing to contribute one day in the week to carry out the activity. The study also found that some explanatory variables, namely, gender of the household head and participation in voluntary service, significantly influenced both households’ willingness to participate and the number of man-days they were willing to contribute to reducing the flow of plastics into the oceans. On the other hand, some explanatory influenced either household’s willingness to participate or the number of man-days they were willing to contribute to reducing the flow of plastics into the oceans. Generally, our study has provided evidence-based information that could help manage the problem of illegal waste disposal and reduce the flow of plastics into the oceans.Following the findings, we can infer that households in Lagos practice illegal waste disposal. However, most households are willing to participate in a clean-up of road gutters/drainage channels programme once a week before the onset of seasonal rains to reduce the flow of plastics into the oceans. Interestingly, the provision of waste management information and dumpsters reduces the likelihood of illegal waste disposal. Also, women and those who often participate in volunteer activities are more likely to participate and contribute more days in the cleanup activities. In addition, large households with highly educated household heads and those that pay more for waste management would contribute fewer days in the cleanup activities. However, enhancing the knowledge of the household heads on the dangers of plastic pollution through well-packaged information on waste management would help increase the number of man-days they can contribute to cleanup activities to reduce the flow of plastics into the oceans. Therefore, to reduce the flow of plastics into the oceans, the government at the local level should make an effort to provide waste dumpsters and mobilize the citizens to clean up road gutters/drainage channels before the onset of rains. Government should provide well-packaged information on the dangers of single-use plastics and plastic pollution to the citizens, especially for the men folks, to enhance their knowledge on the issue and thus discourage illegal waste disposal. It will also encourage them to take action against plastic pollution. Mobilization of efforts for a clean-up campaign should focus mainly on previous volunteers to community clean-up activities, women, less educated household heads, households with additional income contributing members, low waste management fee-paying households. Incorporating these findings in policy and actions against plastic pollution would help reduce the flow of plastics into the ocean.S1 File(PDF)Click here for additional data file.