Tongue squamous cell carcinoma is the most common malignancy in the oral cavity. Despite advances in diagnosis and treatment, the prognosis of advanced states has not significantly improved. Depth of invasion, pattern of invasion such as tumor budding grade, lingual lymph node metastasis in early stages, collective cell migration and circulating tumor cells in peripheral blood are some examples of the mechanisms that are currently receiving increasing attention in the evaluation of the prognosis of tongue cancers. Anatomic-based surgery showed that it is possible to improve loco-regional control of tongue cancer. In patients with a “T-N tract involvement”, there is significantly more distant recurrence (40%) in patients undergoing a compartmental tongue surgery. In general, the neoplastic infiltration of the lingual muscles is traced back to the finding of neoplastic tissue along the course of a muscle; however, the muscle fibers, due to their spatial conformation and the organization of the extracellular matrix, could influence the movement of tumor cells through the muscle, leaving its three-dimensional structure unchanged. We need to exclude the possibility that tongue muscle fibers represent a mechanism for the diffusion of cancer cells without muscle invasion. Tongue squamous cell carcinoma (SCC) is the most common malignancy in the oral cavity; studies show that oral squamous cell carcinoma in young nonsmokers originates primarily in the tongue . DespiteThe tongue can be considered a median muscle organ made up of two equal parts, separated from each other by the median raphe . Tongue Between the muscle fibers there are connective structures that include: the medium septum, a thick sheet of fascia in the midline of the tongue that serves as origin for the transverse muscle; the paramedian septum, fascia that separate the genioglossus muscle from the inferior longitudinal muscle and the lateral septum, and connective tissue that envelopes the inferior longitudinal muscle .Epithelial–mesenchymal transition (EMT) of cancer cells and lymphogenesis of the tumor microenvironment are important events in tumor metastasis in patients with oral tongue squamous cell carcinoma . SeveralIn our experience, the study of macroscopic anatomy of specimens from patients undergoing extensive excision of the tongue tissues and of the related anatomical components, allows the identification of sequential and specific stages of the diffusion of neoplastic infiltration . For sim(A) Initial stagesThe anatomical analysis of the tongue surgical specimens of cancer patients showed that, in the initial stages, the tumor grows in the thin connective structures arranged between the muscle fibers, running parallel to the surface following the architectural texture of the intrinsic muscles. The spaces between the muscle fibers seem to guide the growth of the neoplasia. In our experience as surgeons, these spaces can be viewed as “low resistance anatomical” pathways and upon further analysis considered to constitute migration in confined spaces, where the structural characteristics of the extracellular matrix influence the diffusion of cancer cells. If this working hypothesis were correct, rather than “low resistance anatomical” pathways, these spaces could be construed as a preferential or obligatory path of diffusion of the disease in muscle tissue such as tongue tissue. Some recent research findings appear to corroborate this hypothesis. Cell adaptation to space and space availability together dictate migration efficacy . Additio(B) Late stagesOnce cell tumors reach the transition zone with the extrinsic muscles , the spread in the tongue always follows the longitudinal muscle fibers with cranio-caudal and anterior-posterior progression . In caseIt is reported that in vivo, cells migrate through complex topographies that impose directional choices on cells. However, little is known about the inputs of a directional decision-making process in regions that present cells with different paths for cell migration. Some experimental evidence suggests that when cells reach an intersection, they ‘decide’ to follow the path of least hydraulic resistance, meaning that cells choose the shortest path or the path with wider microchannels . HoweverThe tumour progression along the genioglossus muscles can come close to the septum but maintains a path parallel to it without going over it, always respecting the anatomical integrity, even if in contact. The overrun of the septum with the contra-lateral involvement only occurs along the intrinsic muscles above it. This is because the intrinsic muscles in this area constitute a unique structure that covers the dorsum of the tongue. Consequently, from a surgical point of view, since the lingual septum represents a cleavage and not a resection plane, the progression of neoplastic infiltration along the genioglossus muscle, even if close to the lingual septum, does not require radicalization of the contralateral genioglossus muscle. Even if the anatomical limit represented by the septum is exceeded, it is the anatomical characteristics of the lingual musculature that influence the progression of the contralateral compartment. The neoplasm can exceed the midline only above the lingual septum, spreading along the intrinsic transverse course muscle fibers. Thereafter, there may be an infiltration of the contralateral genioglossus musculature. This implies that, in the first case, a median-based wedge resection of the intrinsic musculature is necessary, while when the neoplasm begins to infiltrate the extrinsic musculature, a subtotal glossectomy is performed which also includes the removal of the contralateral genioglossus, leaving only a functional unit consisting of the tongue base and the hyoglossus muscle.A distinctive feature of progression is the involvement of connective tissue located between the genioglossus and hyoglossus, where the vascular bundle of the hypoglossal nerve passes, and between the hyoglossus and mylohyoid, a connection area with latero-cervical lymph nodes containing the sublingual gland and lingual nerve.When the cancer reaches these areas, the nerves present with a diameter greater than 1 mm facilitate tumor progression along their axis with a perineural path  that acc(C) The “T-N Tract”We have defined the “T-N Tract” as the fibro-fatty tissues that connect the primary to the cervical lymphatic chain containing the neuro-vascular , glandular  and lingual lymph nodes of the floor of the mouth localized on the internal surface of the mylohyoid muscle. The submandibular gland is considered part of the contents of Level IB of the neck and not part of the T-N tract.Regional lymph node metastasis is a major prognostic factor for head and neck cancer because it indicates aggressive tumor biology, as well as representing a source of subsequent metastasis. A comprehensive discussion of the issues inherent in the involvement of cervical lymph nodes in tongue tumors goes beyond our objectives; in this context, we want to focus on the fact that, in addition to the structure of the lingual muscle bundles, it is possible to identify at least anatomically a district with a more lax collagen organization, which due to strategic relationships with numerous lymphatic and vascular structures and nerves plays an important role in the spread of tongue disease.Regarding the patterns of diffusion, the analysis of the T-N tract showed the presence of metastatic lingual lymph nodes and lymphatic metastases “in transit” .We found that in the tongue, and contrary to some reports , the tumA possible criticism of the compartmental approach in the treatment of lingual malignancies is whether improved survival is associated with poor functional outcomes. This aspect was investigated by Grammatica et al. in a recently published study. They showed that compartment surgery does not significantly affect speech. However, especially in the case of combined treatments, subclinical food aspiration and vallecular pouch were present in a significant percentage of patients. Finally, a correct reconstruction represents the key aspect for preserving the lingual strength .In musculoskeletal or parenchymal locations, an “anatomical compartment” has been defined, where the fascia layers act as a barrier to primary tumor invasion, thus tumor spread is forced to follow the orientation of muscle fibers, parenchyma and soft tissues, including nerves and vessels. This is the reason why a single muscle, or a group of muscles, may be considered a “compartment”. Radical and complete removal of this anatomical unit is the aim of compartmental surgery .Consequently, in the clinical setting, it is not possible to separate the effects of a single cellular or tissue activity from the other; for tongue cancer, it becomes necessary to consider other phenomena such as perineural invasion or involvement of regional lymph nodes, in particular lingual lymph nodes . Today wTo reinforce the idea that like smooth muscle invasion, neoplastic invasion of skeletal muscle is associated with worsened cancer prognosis, Beunk et al.  cited thUndoubtedly, we need to improve our basic scientific knowledge and we need to improve our ability to translate as much of our basic scientific knowledge into significant disease altering therapeutic strategies in terms of local, loco-regional, functional and overall survival . For exaFrom this perspective, the study by Beunk et al. allows us to deepen our knowledge of tumor spread in tumor tissue and to fill a large gap in this field . In factIt was reported that clusters of CTCs carrying an elevated risk of metastatic lesions at distant sites and their presence in the peripheral circulation of cancer patients are generally associated with a poor prognosis . AdditioAnatomic-based surgery showed that it is possible to improve loco-regional control of tongue cancer. However, in patients with a “T-N tract involvement”, there is a significantly more distant recurrence (40%) in patients undergoing a compartmental tongue surgery. In general, the neoplastic infiltration of the lingual muscles is traced back to the finding of neoplastic tissue along the course of a muscle; however, the muscle fibers, due to their spatial conformation and the organization of the extracellular matrix, could influence the movement of tumor cells through the muscle, leaving its three-dimensional structure unchanged. We need to exclude the possibility that tongue muscle fibers represent a way for diffusion of cancer cells without muscle invasion.


The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases  are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two setpoints. This way of operating batch freeze-dryers is shown to be time consuming and inefficient. A model-based optimisation and real-time control strategy that includes model output uncertainty could help in accelerating the primary drying phase while controlling the risk of failure of the critical quality attributes (CQAs). In each iteration of the real-time control strategy, a design space is computed to select an optimal set of CPPs. The aim of the control strategy is to avoid product structure loss, which occurs when the sublimation interface temperature ( Pharmaceutical freeze-drying or lyophilisation is a dehydration process mainly used for stabilizing parenteral therapeutical agents contained in aqueous solutions. By removing most of the water, the shelf-life of the product is prolonged significantly because water drives many destabilization pathways. Since, freeze-dying is a low-temperature process it is a very popular processing technique for heat-labile biological drug substances. Therefore, many of the approved biopharmaceuticals by the FDA and EMA are stabilized by lyophilisation . HoweverThe freeze-drying process consists of multiple consecutive phases. After loading the vials, the shelf temperature is lowered gradually to freeze the liquid in the vials. Next, the chamber pressure   which was retrofitted with PR-4114 programmable logic controllers (PLC)  and a Pro-Face AGP3000  Human-Machine Interface with Modbus TCP/IP communication capabilities. To keep the condenser temperature, shelf temperature and chamber pressure at their predetermined setpoints, multiple ON-OFF process control loops were programmed on the PLC. Hereto the freeze-dryer is supplemented with resistance temperature detectors in the condenser and shelf fluid system, and two different pressure gauges in the drying chamber. To measure the product temperature directly three additional thin gauge type-K thermocouples  were available in the drying chamber. To measure chamber pressure both a Pirani and Capacitance pressure gauge are present, yielding the opportunity to apply a comparative pressure measurement methodology . Due to For the the purpose of supervisory control and data acquisition (SCADA), an additional remote computer was installed with LabVIEW 2017 including the NI-DSC module  to communicate with the freeze-dryer PLC using Modbus TCP/IP. A state-machine based application was developed in the LabVIEW software to drive the freeze-dryer through all sequential freeze-drying steps, i.e., freezing, condenser preparation, primary drying initialization, primary drying with optimisation and control, secondary drying and venting/stoppering. Please note that the proposed strategy used for primary drying was implemented in MATLAB 2018a using the Parallel Computing Toolbox  which had to be integrated in the LabVIEW application.A mechanistic model describing the primary drying phase of pharmaceutical vials in a traditional batch freeze-dryer is the core of the real-time optimisation and control strategy. This mechanistic model has been described thoroughly in the literature . The moda and b are constants to convert to SI-units [M the molecular weight of water [kg/mol], Here, SI-units , Ap and b and Ti .Furthermore, the maximum allowable sublimation rate ow model . The latThe vial inner radius The heat transfer coefficient Equation .(4)Kv=mWith Equation , Kv coulThe dry layer resistance Equation  with Rp0To determine these coefficients as well as the variability of Equation . Next, TEquation ). FinallEquation ).(7)Rp=With With With Once the six Equation . Please The variability of the vial filling volume The variability of the outer radius The critical temperature Since sublimation requires a deep-vacuum, the chamber pressure should be lowered at the start of the primary drying phase using a vacuum pump. The initial pressure drop from atmospheric pressure until the start of ice sublimation was predefined taking the machine limitations into account. To have a robust estimation of this characteristic pressure decrease curve, ten repetitive runs were performed between atmospheric pressure and the minimal achievable pressure (7 Pa). Above 130 Pa, the Pirani sensor value The supervisory application programmed in LabVIEW starts with a freezing phase which is programmed according to a fixed protocol, i.e., list of setpoints for the shelf temperature To start the primary drying initialization phase, the last se curve  with a tThrough the application of uncertainty analysis (UA) to the primary drying model , a desigThe UA starts off by defining a machine capability space. This space spans the multivariable combination of the manipulated variables which can be achieved taking into account the previous operating setpoint. Please note that in this case the two manipulated variables of interest are Next, Monte Carlo simulations are performed to estimate the uncertainty of the primary drying model outputs. Accordingly, a model parameter space is constructed by sampling a fixed number of parameter combinations puts see . For ro, moments . Note thAll points within this parameter space were subsequently used to solve the primary drying model for Equation  which waIn the next step, the model output space was sub-sampled using the machine capability grid of oint cf. . This rehe model . Which mFor each grid point the sub-population in Ultimately, the refined grid was used to evaluate the primary drying model together with nominal input parameters to obtain an estimate of Based on the dynamic design space constructed by the UA it is possible to control and optimise the primary drying phase of a freeze-drying process taking into account a defined and accepted risk of failure (RoF). To do so, a supervisory control strategy is implemented on top of the existing low-level control loops of the freeze dryer, i.e., the ON-OFF controllers for The presented strategy is based on the receding horizon principle, i.e., optimal process conditions in the near future are calculated using information of the past and a cost function. Depending on the chosen sampling interval erformed . Please For each optimisation in the receding horizon, the variability of the manipulated variables  upfront  and therBesides the optimisation of It is important to remember that two groups of vials were identified earlier based on their distinct heat transfer properties . This exOnce the end of primary drying is reached, the optimisation and control strategy is automatically stopped. Please note that both the comparative pressure measurement and the uncertainty analysis have to indicate the end of primary drying before starting secondary drying. In this case the pressure signals from a Pirani gauge ed batch . Please ajectory .The secondary drying phase is programmed according to a fixed protocol. To verify the proper functioning of the proposed optimisation and control strategy for primary drying, six independent freeze-drying runs were performed at a pre-defined accepted Risk of Failure level of 0.1%, i.e., the predictions for a defect .To verify sublimation front temperature predictions Equation  16]. Du. DuTi inThree out of six verification runs were performed without the application of intended process disturbances. This to solely demonstrate the functioning of the proposed real-time optimisation algorithm. For the other three runs, multiple disturbances were intentionally introduced both in the temperature and pressure loops of the freeze-dryers. The objective of these disturbed trials is to evaluate the performance of the system check introduced on the machine capability space. This should assure that the proposed real-time optimisation strategy is able to keep the product safe in the presence of uncontrolled events. Because these disturbances were introduced as disturbed setpoints to the low-level control loops, they are out of the direct control of the optimisation algorithm. These disturbances are therefore only noticed when The characteristic heat transfer coefficient findings ,20,24. Tal group . This alThe regression for quations –13) on  on Rp agEquation . This leterature ,27. The The standard deviation of Variation on other model parameters  was meascollapse . The drilost yet . Upon heThree normal operation verification experiments were performed to verify all functions of the primary drying optimisation and control strategy. The UA, using parallel computing, with 10,000 samples and a After freezing and preparation of the condenser and vacuum pump, primary drying was initiated by lowering the pressure according to the pressure curve depicted in nitiated . At the Please note that after approximately 17.9 h in the primary drying phase, the UA estimated that all edge vials were dry. This because all the samples of the optimal grid point had a condition of The absolute difference between the setpoints of the low-level ON-OFF controllers and the observed values were used as a term of variation for By including the variation of eight different sources, the UA was capable of estimating an uncertainty on the calculated value of At last, an observed Equation ). When fThe results for a verification run with process disturbances is given in Regarding the product temperature, a similar conclusions can be drawn for the disturbed verification runs as for the undisturbed runs. This begin the fact that for both the centre vials  and the edge vials , the observed In  product . Aside o77 h see .As expected, the endpoints of the disturbed verification runs are less precisely located. It appeared that there exists a strong correlation with the relative extend of the applied disturbances. Nevertheless, the location of the endpoint predictions according to the UA are analogous to the normal operation runs as they are situated between the midpoint and the offset of the The observed In the case of the 99.9% upper percentile of The endpoint of primary drying evaluated with thermocouples was perceived earlier then the UA prediction. However, it should be noted that the former are not the most accurate method to determine the end of primary drying since they are based on point measurements in a single vial . Moreovef Pratio . The midl et al. .A critical aspect of this work was to reduce the computational load of the real-time calculations. To solve this some practicalities such as sub-sampling, empirical fitting of the Because the process is steered towards the edge of failure without crossing it, it appeared that the proposed optimisation and control strategy is very dependent on the model parameter values. The accuracy of the predicted Equation  describeried see . Howeverried see  is not cerfectly . More deRecently new methodologies are being proposed to optimize batch freeze-drying by implementing dynamic settings during primary drying . When a Multiple experimental verification runs, with and without induced process disturbance, were performed on a batch freeze-dryer with a predefined RoF of 0.1%. During these experiments the manipulated variables


This study aims to calculate the costs of prostate cancer radiotherapy in a regional hospital Department of Radiation Oncology equipped with Three-Dimensional Conformal Radiation Therapy (3D-CRT) and Intensity Modulated Radiation Therapy (IMRT) Volumetric Arc Therapy (VMAT) radiation technology, using activity based costing (ABC), and to compare the costs of both methods at the level of component treatment process activities and with respect to insurance reimbursements. The costing was performed based on a sample of 273 IMRT VMAT patients and 312 3D-CRT patients in a regional hospital in the period from 2018 to 2019. The research has highlighted the necessity to place emphasis on factors that may skew the costing results. The resulting output has been supplemented by a sensitivity analysis, whereas the modeled parameter is represented by the time required for one patient fraction on a linear accelerator and the time the Radiology Assistant needs to prepare the complete radiation plan as part of radiotherapy planning. Moreover, the effects of the received grant, in the form of calculated write-offs, are also considered. The case study uses the example of radiotherapy to demonstrate the potential of ABC and suggests considering the application of this method as an effective management tool for cost and economic evaluation as part of comprehensive hospital assessment under the Hospital-Based Health Technology Assessment (HB-HTA) initiative. Recently, a growing interest in Hospital-Based Health Technology Assessment (HB-HTA) methods has been observed, since it can provide important support for decision-making in the area of purchasing, implementation and/or disinvestment of technologies or interventions in hospitals ,2. In moActivity based costing (ABC) appears to be a suitable management tool for these purposes . It provThe incidence of prostate cancer varies dramatically across geographic locations. Nearly 70% of newly diagnosed patients reside in developed countries. The highest incidence of this disease has been observed in Australia, New Zealand, North America, and in Northern and Western Europe. Southern Asia is currently a region with the lowest incidence of prostate cancer, which has, however, been on a sharp increase over the past 20 years . Since 1With the introduction of screening using PSA testing, it is now possible to monitor the disease in its very early stages and detect small and low-risk prostate cancers that do not otherwise manifest clinically in the patient’s day-to-day life. PC patients currently have three main treatment options to choose from. The therapeutic approach to localized low-to-medium risk prostate cancer involves a conservative method of active surveillance. This method consists of regular patient check-ups, transrectal ultrasound (TRUS), a PSA blood test about every six months and tumor tissue biopsies done at 18-month intervals. In this way, curative treatment is delayed until the patient meets the criteria for classifying the progression of the disease .If the disease progresses or if active surveillance is impossible or even undesirable, other options for curative treatment will be considered. In current oncological practice, external beam radiotherapy, along with interstitial brachytherapy and radical prostatectomy, is one of the principal methods of curative treatment for localized and locally advanced prostate cancer. External beam radiation therapy (EBRT) is the most common type of radiation therapy used for cancer treatment, while the linear accelerator  is the most frequently used irradiator .Implementation of the selected treatment strategy is preceded by a series of mandatory staging examinations, including digital rectal examination (DRE), TRUS, PSA testing, prostate biopsy, a lesser pelvis CT (computed tomography) scan for pelvic node examination, MR examination of the abdomen, and pelvis to determine the T stage, or a combination of both modalities. A liver ultrasound scan and an X-ray of the lungs in patients with PSA > 20 ng/mL is also required to rule out generalization. A surgical report must be issued for all patients who undergo surgery. Bone scintigraphy should also be used in the staging of patients with suspected distant metastases (with PSA > 10 ng/mL). Appropriate treatment is then recommended based on prognostic factors. The extent of the disease (staging) is determined based on TNM , histology including the Gleason Score, the initial level of increased PSA values and the dynamics of changes in the PSA level, grouping the patients into the following risk categories according to Adjuvant irradiation of the prostate bed is recommended for patients with risk factors relating to RAPE . The occurrence of pelvic lymph node metastases is also a negative factor in the prognosis, in which case it would be appropriate to apply external irradiation in conjunction with long-term androgen deprivation therapy (neoadjuvant/concomitant/adjuvant).Both of the radiotherapy techniques being assessed (3DCRT and MRT VMAT) can deliver highly conformal radiation and allow for the application of high radiotherapeutic doses to destroy the tumor tissue while sparing the surrounding vital organs, which in the case of prostate cancer include mainly the urinary bladder, rectum, small intestinal loops and femur heads.Prostate cancer patients treated with hypofractionated accelerated radiotherapy (HART), using the IMRT VMAT method, receive the overall treatment within a shorter period of time. Moreover, the toxicity associated with prostate cancer treatment is effectively reduced, resulting in a lower incidence of both acute and late adverse responses to radiation. The reduced occurrence of gastrointestinal toxicity is amply supported by the respective study .Globally, prostate cancer (“PC”) is the second-most frequently diagnosed oncological disease in men, while, on the imaginary scale, it is the fifth-leading cause of cancer-related death in males. It accounts for approximately 6.6% of all oncological deaths. Prostate cancer globally comprises 15% of all oncological diseases, imposing a significant burden on the public healthcare system .Developments in radiotherapeutic technology have allowed for higher radiation conformity of an irregular target volume and dose escalation, which has a measurable impact on treatment results ,19,20,21Hypofractionation modes contribute to both reducing the duration of radiotherapy and mitigating the toxic effects of PC therapy, as well as curtail the occurrence of the acute and delayed side effects of radiation. Numerous results validating the advantages of IMRT have already been presented in a wide range of randomized studies. For example, Ślosarek  has demoIMRT has seen its use in the treatment of tumor diseases via radiotherapy increase severalfold in the past 20 years. In the Czech Republic, the proportion of each method applied to the treatment of PC is unknown; however, given the required components and the precise technical specifications of individual radiotherapy clinics, all of these facilities can be assumed to possess the capabilities necessary to provide IMRT-based treatment.It goes without saying that the introduction of these novel methods as standard for the treatment of tumor diseases is associated with substantially higher costs. The clinical operation and technical maintenance of the state-of-the-art IMRT linear accelerator components is financially challenging, but is should be noted that a portion of these costs would be compensated for by the improved treatment results, reduced treatment time and lower costs for the treatment of complications related to gastrointestinal toxicity. A study conducted by Schroeck et al.  indicateIn order to obtain an accurate estimate of the total costs of radiotherapy treatment of patients with the C61 diagnosis, the second most common oncological disease, right after breast cancer in women, hospitals would do well to monitor the flow of both direct and indirect costs across the activities conducted as part of the entire process of radiotherapy in relation to both irradiation technologies to avoid inaccurate conclusions. For this, the ABC method, which is used widely across industries, appears to be the ideal tool.Application of the ABC method to the healthcare sector requires that all specifics involved be considered. These specifics are generally defined by Popesko , for exaThere is small number of studies that show how to monitor the real cost of diagnosis in healthcare facilities, and which also summarize the factors that have a significant effect on the overall calculation result, or diminish the informative value of the result.This study aims to determine the costs of prostate cancer radiotherapy in a regional hospital Department of Radiation Oncology equipped with 3D-CRT and VMAT radiation technology, using the ABC method with a view to comparing the costs of both methods in general and also with respect to insurance reimbursements. The secondary objective of this study is to examine the effect of selected calculation parameters, using the sensitivity analysis to model various scenarios. The input parameter of the sensitivity analysis is represented by the time required for one patient fraction on the linear accelerator and the time the Radiology Assistant needs to prepare one complete radiation plan as part of radiotherapy planning. Furthermore, the case study calls attention to the significant impact of grant schemes directly related to the amount of write-offs included in the ABC calculation. It is the amount of these write-offs that can significantly bias the result of the overall calculation.All input data have been gleaned from the records of a regional hospital with 46 departments and total capacity of 973 beds. Employing 2708 staff members, the hospital provides medical care to approximately 460,000 patients. The range of inclusion criteria for this case study has been limited to include only information on patients with a confirmed C61 diagnosis. The reference period was the period of 2018–2019, with the cost data on the 3D-CRT technology operation referenced to 2018 and IMRT data to 2019 as the latter technology had only recently been included in the treatment routine. Both irradiation technologies used a linear accelerator (LA) supplied by Elekta Services, s. r. o. To recalculate the data and adjust them to the same basis, the input data for 2018 were discounted in a manner similar to other authors ,31,32. FThe Department of Radiation Oncology made available all required information regarding its patients treated using external radiotherapy with photon beam radiation during the reference period. The basic input data include information concerning, in particular, the total hospital costs, separate radiotherapy department costs and staffing levels, pay levels, number of patients, and the volume of procedures/interventions with respect to both radiotherapy technologies. Additional economic data were gleaned from the internal Oracle Business Intelligence system and the Medicalc information system, while non-financial indicators were obtained from the Mosaiq oncology verification system. See The default chart describing the component phases of the ABC method is based on Popesko et al.  recommenThe determination of activity unit costs (JNA) constitutes a kind of intermediate stage in the conversion of activities to cost objects, expressed as a ratio of total costs of activities to the measure of their performance/output. The denominator in the formula for JNA calculation varies according to the character of each activity . The unit costs of an activity are calculated according the following formula:The labor costs of a given activity (CPA) are determined based on the following relationship:See the following chart in The basic input information for the ABC calculation is the cost item overview for the entire department for both reference periods, see Component activities were defined as part of the second phase. See Direct costs also include direct labor, further allocated based on the actual time spent on each activity. In addition, specific costs that cannot be attributed to any activity should be set aside from the identified total costs. The cost items removed for this purpose included travel expenses and the road tax as these costs would unnecessarily skew the ABC model output. Indirect costs have been assigned to individual activities based on the actual consumption ratio related to specific activities, see below. The costs are further categorized into: primary costs , secondaFurthermore, it is essential that any secondary costs be factored into the costing model .The output of this phase is the Activity Cost Matrix developed based on suitable cost drivers. A key was used in the process of cost allocation to activities, see The labor cost matrix was calculated using the formula (2). For a summary see All allocated cost items were schematically entered into the cost-activity matrix with reference to cost drivers. The following table shows the cost-activity matrix for 3D-CRT and IMRT technologies . The tabThe above information also lends itself to graphic representation. As clearly shown in In this phase, the main output is the costing per unit of activity, see The total costs of an activity can be determined by multiplying the unit cost of the relevant activity by the activity’s performance rate. The sum of costs of A1 to A5 component activities represents the amount of the actual costs incurred in connection with the complete radiotherapy treatment of one patient using either the 3D–CRT technology (2062 EUR) or the IMRT (intensity modulated radiotherapy) technology (1479 EUR), see See IMRT costs are lower with regard to both unit and annual costs. In either case, the costs of treatment are lower than the amount of insurance reimbursements. It should be noted that the differences in reimbursements are due to the different number of patients, point value deviations and the way in which the code 43633 is reported to health insurance companies. The 43633 code per one radiation treatment was reported seven times for the 3D-CRT technology, which corresponds to the number of actual radiation fields. With the arrival of the more advanced IMRT technology and in line with recommendations of the professional society for oncology, the 43633 code per irradiation treatment began to be reported 10 times, the reason being that the process involves innumerable fields with modulated radiation beam intensity in one swing of the gantry.If all radiation fractions were extended or reduced by just one minute, the labor costs related to A5—Radiation would be by 16 EUR higher/lower, which in turn represents an increase/decrease in costs by 5163 EUR for the target group of 312 patients treated with 3D-CRT. With the application of IMRT, this extension or reduction in the time of radiation would amount to 12 EUR per radiation set, which would increase or decrease the overall costs of treatment of a group of 273 prostate cancer patients by 3284 EUR. See The time with respect to RT planning (A3) was analogically modulated. If the duration of the radiotherapy plan processing was 10 min longer, the costs related to 3D-CRT treatment would only increase by 441 EUR for a total of 312 patients, while the change in duration with respect to IMRT would result in an even more moderate increase of 195 EUR for a total of 273 patients. Needless to say, these values necessarily vary depending on the number of medical staff and the number of patients treated during the reference period. However, the impact of the time factor at the level of this activity is negligible in terms of costs.The resulting cost balance is affected by the EU aid scheme  related to the Integrated Operational Program (IOP). The grant provided for the acquisition of two linear accelerators and a water phantom system amounted to more than 2,017,000 EUR. The grant accounts for 85% of the total purchase price, with the remaining 15% funded from the organization’s own resources. This fact must not be disregarded when using ABC costing, which shows modeling for various levels of the amount depreciated for 3D-CRT technology in 2018 see .The modeling can also be conducted for IMRT technology for 2019 by analogy, see As the results show, in the case of 100% funding from own resources, insurance reimbursements exceed the actual costs of C61 diagnosis.Despite the increasing incidence of both malignant and benign prostate tumors with consistently lower mortality rates over the long term, mainly due to prevention and early diagnosis, oncology treatment represents a significant portion of public funds spending due to the massive volume of new cases. The rising incidence of prostate cancer can be attributed primarily to the introduction of screening tests, early diagnosis and also to population aging, as old age is one of the main risk factors responsible for the incidence of oncological diseases. Improvements in the quality of both diagnostic and treatment methods essentially go hand in hand with the rising costs of healthcare. In the field of radiation oncology, external photon beam radiotherapy is perceived as a particularly costly approach to the treatment of oncological diseases. Thanks to the dramatic technological advances seen in radiation oncology, there has been a substantial shift in the accuracy and patient safety of target volume irradiation in recent decades, while keeping the level of treatment-related toxicity within acceptable boundaries with minimum damage to critical organs. That is why radiotherapy using linear accelerator (LA) is currently commensurate with surgical treatment and prostate cancer patients have been increasingly prone to opt for external radiotherapy due to both its non-invasive approach and highly curative effect. As the high costs of radiotherapy treatment  require This study uses the example of a regional hospital to describe the costing process for the C61 diagnosis and endeavors to identify any potential pitfalls and factors with a discernible impact on the final results of the calculation. At the same time, it seeks to highlight the discrepancy between the actual costs of diagnosis and insurance reimbursements. A similar discrepancy can be observed, for example, in the Bauer-Nilsen study  entitledABC is the preferred method to estimate the costs of radiotherapy, especially when comparing radiation techniques. The application of this method was successfully published in study of Yong et al. , Poon etThis study compared the two different treatment techniques for the hospital internal purposes to accommodate a request submitted by its management for the evaluation of the cost data for both of these modalities. As has already been mentioned, the clinical efficiency with respect to IMRT is beyond question, as is further corroborated through studies by Yong et al. , Carter In view of the selected indicators, the applied fractionation modes, including dose distribution and the length of time required to perform specific activities seem to be the most significant in terms of affecting the resulting costs of individual radiotherapy techniques. It is equally important to take into account the number of irradiated patients, which varies with the radiation technology used. The greatest time consumption and a sizable percentage can be clearly seen in relation to A5 and A3 activities. Both of these activities are, to a large extent, conducted by Radiology Assistants whose time spent on a particular procedure is predetermined. However, it is during these activities that accidental increases in time consumption are most likely to occur . Delays on the part of the patient are often caused by inadequate bladder or rectum preparation, which is essential to ensure effective treatment and prevent unwanted movement during radiation. In the event of excessive weight loss or deterioration in the clinical condition of the patient, necessitating an interruption of the radiation set, the radiation plan, including the localization CT, should be resimulated or a new plan prepared. While the proportion of individual on-site factors is unknown, their occurrence is routine. In order to determine the way in which time consumption of the two most demanding activities affects the costs of the radiotherapy as a whole, a sensitivity analysis was carried out, modifying the time required for one patient fraction on the linear accelerator and the time the Radiology Assistant needs to prepare the complete radiation plan as part of radiotherapy planning. The results indicated that radiation time adjustment at the level of A5 will cause a relatively substantial impact on the costs .The level of acute and late gastrointestinal (GI) and genitourinary(GU) tract toxicity in prostate cancer patients treated with radiotherapy was determined using RTOG/EORTC, a scoring system developed by the Radiation Therapy Oncology Group (RTOG). A sample of patients treated with IMRT/VMAT reported fewer cases of both acute GI toxicity  and GU toxicity . For a more comprehensive evaluation of patient outcomes, it would be appropriate to also take into account the late responses to radiation by the surrounding tissues and organs. However, in order for the comparison to be credible, two equivalent plans would have to be created for each irradiation technique with identical radiobiological efficiency and subsequently summarized based on dose volume histograms. What is more, late gastrointestinal and genitourinary toxicity related to cancer radiotherapy treatment occurs with a delay of several years and no clinical trials pertaining to this study are yet available.Therefore, when applying ABC costing to hospitals, it is essential that the specifics of each organization and all factors likely to influence the costing results be identified and carefully considered. These results cannot be regarded as either unequivocal or applicable to other organizations. As already mentioned, major effects include the time factor, which operates at the level of A3 and A5 activities, and the amount of own resources used to purchase the technology, reflected in the amount of depreciation included in the calculation.The inclusion of Activity Base Costing in standard procedures as part of HB-HTA can contribute to systematic cost and economic evaluation . However, the systemic implementation of the ABC method must be done in such a way so that this HB-HTA “good practice method” could be easily adopted by other hospitals (transferability), as pointed out by the EU initiative .The costs per patient with C61 diagnosis treated using the 3D-CRT and MRT technologies amounted to 2062 EUR and 1479 EUR respectively. The annual costs of 3D-CRT (312 patients) amount to 643,344 EUR and, in the case of IMRT (273 patients), to 403,767 EUR. As the results show, IMRT appears to be the less expensive technology of the two addressed in this case study. However, the results of the sensitivity analysis also need to be taken into account. The sensitivity analysis indicates that changes in the time parameter will significantly affect the resulting calculation. This is especially noticeable with regard to the A5 activity. If all radiation fractions were extended or reduced by just one minute, the labor costs would be 5163 EUR higher/lower for the target group of 312 patients treated with 3D-CRT. With the application of IMRT, this extension or reduction in the time of radiation would increase or decrease the overall costs of treatment of a group of 273 prostate cancer patients by 3284 EUR. Another important factor affecting the overall costs related to the C61 diagnosis is the grant amount awarded to the hospital. The case study presupposes a situation wherein the grant covers 85% of the purchase cost, affecting input write-offs. Accordingly, the resulting values of the total costs with respect to C61 are lower. If the write-off amount included the full costs of the linear accelerators, the total costs of C61 would more than double. However, in the case of this medical facility, insurance reimbursements would exceed the actual costs incurred by the hospital for this diagnosis even if 100% of the funding came from its own resources.


The size distribution of adipocytes in fat tissue provides important information about metabolic status and overall health of patients. Histological measurements of biopsied adipose tissue can reveal cardiovascular and/or cancer risks, to complement typical prognosis parameters such as body mass index, hypertension or diabetes. Yet, current methods for adipocyte quantification are problematic and insufficient. Methods such as hand-tracing are tedious and time-consuming, ellipse approximation lacks precision, and fully automated methods have not proven reliable. A semi-automated method fills the gap in goal-directed computational algorithms, specifically for high-throughput adipocyte quantification. Here, we design and develop a tool, AdipoCyze, which incorporates a novel semi-automated tracing algorithm, along with benchmark methods, and use breast histological images from the Komen for the Cure Foundation to assess utility. Speed and precision of the new approach are superior to conventional methods and accuracy is comparable, suggesting a viable option to quantify adipocytes, while increasing user flexibility. This platform is the first to provide multiple methods of quantification in a single tool. Widespread laboratory and clinical use of this program may enhance productivity and performance, and yield insight into patient metabolism, which may help evaluate risks for breast cancer progression in patients with comorbidities of obesity.ABBREVIATIONS: BMI: body mass index. Breast cancer incidence, progression and mortality continue to pose a serious public health challenge, particularly among underserved patients and in safety net hospitals , where tIt has been long appreciated that obesity and metabolic disease disproportionately affect underserved patients ,12, for Although transcriptional profiling of patient primary tumour tissue , or the We have used antibody capture assays to profile plasma cytokines of metabolically at-risk patients with obesity to develop signatures of cytokines known to drive breast cancer progression and metastasis . Yet, weAnalysis of adipocyte size distribution in adipose tissue samples has been a popular practice for researchers looking to use histological samples to gain insight into metabolic and immunological conditions . Adipocy2). The time required to perform these analyses using the hand-tracing method is largely proportional to the number of cells quantified. For large volume or high-throughput sampling, the method is highly inefficient and time-consuming. Overall, the utility of the hand-tracing method for high-throughput adipocyte quantification is limited because it is tedious, inefficient and dependent on the skills of the operator, which introduce human error and subjectivity [Comparison of current adipocyte quantification methodology from digital histological images reveals two primary, well-established methods and one emerging method: hand-tracing and ellipse approximation have been widely used and described for adipocyte quantification, and fully automated image analysis remains an emerging technique ,30,31. TArea = π*A*B [The ellipse approximation method is also described in immunology research publications , whereby = π*A*B . HoweverThe third method that has been and continues to be explored in the literature as an emerging technique, fully automated quantification, seeks to enable high-throughput measurement of adipocytes without, or with minimal intervention from a user. Such tools leverage multiple layers of image manipulation, processing such as converting to binary and setting an intensity threshold, and segmentation to calculate adipocyte size by the area contained in the boundary detected and subtracted from the background . AlthougEarly and current methodology of adipocyte quantification are problematic and insufficient, and fail to reach a compromise between accuracy, efficiency and robustness, which affects the productivity of the user and the potential of adipocyte quantification as a prognostic indicator ,29. WithHere, we describe the development of AdipoCyze and use the tool to assess the accuracy and speed of adipocyte quantification using the novel, semi-automated tracing algorithm, compared with methods of standard practice, hand-tracing and ellipse approximation.A semi-automated method that allows the user to select cells of interest with ‘one click,’ while all measurements, calculations and renderings are performed through computational algorithms, may fill the need in adipocyte quantification and offer a solution to the challenges described. By enabling high-throughput quantification of both optimal and sub-optimal histological samples, minimizing errors, improving accuracy and increasing efficiency, we expect this novel approach to enhance the productivity of the user.The availability of and widespread adoption of AdipoCyze may usefully inform the standard of care in risk management of obesity-associated cancers, as well as other clinical approaches where adipocyte size measurements are beneficial, such as after bariatric surgery. The tool is well suited to low-resource settings and could assist with prognosis and risk stratification for vulnerable or underserved breast cancer patients, who suffer from increased co-morbidities including obesity, diabetes and hypertension.https://virtualtissuebank.iu.edu/), which is accessible to the general public. Self-reported race of all subjects recruited to this study was African American; all subjects were female. These samples provided a range of sizes to permit the computational algorithm to be developed and tested across a diverse set of samples with varying degrees of quality in sample preservation.The Komen Tissue Bank collected detailed medical history, including diagnoses and medications, from a non-clinical, volunteer population. This information was obtained for each subject in the analysis, stripped of HIPAA identifiers and used with written permission from the Komen Tissue Bank. The donated samples were collected with informed consent following Helsinki guidelines. Protocols, including laboratory procedures used in the study, were submitted to and approved by the Institutional Review Board, Boston University. The data are archived in the Virtual Tissue Bank  at the Simon Cancer Centre (Indiana University). Sections had been stained with H&E and captured as digital images by microscopy. Full-slide digital images of histological breast adipose samples obtained from Komen for the Cure were imported as.svs files, native to Imagescope software. The image files were converted to.tiff and subsequently.jpeg to maintain a high quality and adequate compression for computational analysis. Samples of regions of interest were segmented from each image at constant magnification.AdipoCyze was developed using MathWorks MATLAB suite R2013b. Functional requirements included an intuitively designed, interactive, graphic user interface (GUI), a simple process to import and transform histological image files, the ability to analyse the image using three available quantification methods such as, Trace mode (TM), hand trace (HT), and ellipse approximation (EA), and the ability to export results upon the completion of analysis. The program was constructed to export results in relevant file formats for tertiary analyses . The final program executable file (.exe) was compiled using MATLAB Runtime Complier for distribution and execution on PCs with or without MATLAB installed.The semi-automated cell adipocyte quantification method was designed to allow the user to select cells of interest with ‘one click,’ while all measurements, calculations, and renderings were to be performed through computational computer algorithms. We designed a user experience such that in the Tracing Mode, the user clicks the approximate centre of the cell of interest and the algorithm traces the interior perimeter of the cell using a recursive tracing algorithm. The interior cross-sectional area of the cell is then calculated in square pixels, the calculated region is displayed and the cell of interest is labelled for analytical purposes. In order to use the trace mode with one-click tracing algorithm, the image of interest is required to be transformed using the default transformation parameters in AdipoCyze or manually, following the three-step process of modulating low levels and shadows, converting to binary, and despeckling.We sought to design a hand-trace mode that mirrored the conventional method to be included into AdipoCyze. In this mode, the user is able to manually trace the perimeter of the cell of interest by selecting its vertices by hand. The drawn area is dynamically displayed such that the user is able to visualize the area enclosed. The interior cross-sectional area of the cell is then calculated in square pixels and the cell is labelled for analytical purposes.π*A*B, where A and B are the semi-major and semi-minor axes, respectively. Cells are labelled for analytical purposes.The goal of the ellipse approximation module was to provide users with the option to use the ellipse approximation method to quantify adipocytes, should the analysis or goal of research demand. In this regard, we developed an analysis module such that the user measures the major axis of the ellipse by assessing the size, curvature and orientation of the adipocyte. After the drawing of the major axis, a perpendicular line is projected from the centre of the cell to allow the user to define the semi-minor axis. The interior cross-sectional area of the ellipse approximation is then calculated in square pixels using the equation, Cells 1–15 of the sample were analysed, in order, three times over using each of the adipocyte quantification methods available from the AdipoCyze tool. All cells were measured in the same order and time in between measurements of each cell was recorded in seconds.Cells were measured manually by clicking on the perimeter of the cell to create the first vertex of the polygonal area. The user double-clicked to complete the measurement of an individual cell. Timing was measured from the point at which the initial image loaded in AdipoCyze and analysis can begin to the point in time when the full analysis of the 15 cells was complete. Splits of analysing individual cells were also measured.Cells were measured by approximating an elliptical area over the cross-sectional area of the adipocyte of interest. The user clicked the vertices of the cell to measure the major axis of the ellipse where then a semi-minor axis was drawn perpendicular and through the centre. The area of the ellipse was calculated with the equation: π*A*B, where A and B are the semi-major and semi-minor axes, respectively. Timing was measured from the point at which the initial image loaded in AdipoCyze and analysis can begin to the point in time when the full analysis of the 15 cells was complete. Splits of analysing individual cells were also measured.Analysis using the trace mode first required the sample image to be transformed; the following parameters were applied: Low Level in: 0.9; Shadows: 0.15; Binary Threshold: 0.8; Despeckle Pixel Radius: 5; Number of Passes: 5. To measure cells using the tracing algorithm, the user clicked anywhere in the interior of a cell of interest. The tracing algorithm finds the interior boundary of the cell membrane and traces the interior perimeter of the cell to measure cell perimeter and cell area. Utilizing the tracing algorithm requires transforming the image in AdipoCyze. Time was measured from the point at which the initial image loaded in AdipoCyze and image processing was initiated to the time when the full analysis of the 15 cells was complete. Splits of analysing individual cells were also measured.solid-line border represents an optimal sample containing adipocytes characteristically shaped with structured cell membranes, well-defined borders, and absence of cellular or foreign artefacts. Sub-optimal samples are represented in the subsequent enclosed sections. The area enclosed in the dotted line border and the area enclosed in the dashed line border depict the presence of morphological signatures and cellular artefacts. The area enclosed in the long-dash border contains poorly defined adipocyte cells with deteriorated cell membranes, indicative of poor fixation or nonuniform slices that are too thin for adipose tissue.Samples from the Komen Tissue Bank were analysed and yielded a wide variety of intra-sample heterogeneity, representing a variety of sample quality. As shown in The output of analysis performed using AdipoCyze can be seen in The AdipoCyze Graphical User Interface (GUI) in trace-mode is shown in 2) by cell, in the order of cells measured are shown in Each cell was analysed three times using each analysis method. The results of analysing adipocyte size  2 of 0.89 reveals a correlation weaker than that of  but stronger than that of . The positive intercept of the linear regression confirms observations from 2 value was the highest at 0.992 demonstrating the strongest explanation of the data by the linear fit.Concordance was evaluated based on slope and correlation coefficient of trendlines in The HT and EA methods took the longest time to complete, measuring 15 cells. The TM method took less than one-quarter of the time to complete measuring cells in comparison to the HT method, and nearly half than that of the EA. The time to measure the first cell was similar between the HT and the EA methods, and the longest with the TM. Linear trendlines are displayed on each series of data. Both the HT and EA methods demonstrated evidence of a linear relationship, whereas the TM showed evidence of a non-linear relationship with time, likely due to the time spent upfront to transform the image. Extrapolating the results shown here for the measurement of 15 cells, it would be expected that the gap between time to measure using TM and HT and EA methods increases with higher volumes of cells.When specifically comparing the measurement methods in a heterogenous adipocyte image sample in Figure S1, we saw that both the ideal cell and the non-ideal cell were able to be measured with each method. Visual inspection of the regions calculated revealed that TM was able to closely trace the interior contour of the ideal cell and closely resembles the region calculated from hand-tracing . Consistent with other observations, the ellipse approximation method appears to over-estimate the cell area as the region calculated from ellipse approximation by including regions in the area calculation that are not part of the cell . When non-ideal cells are measured, we see higher variability in measurement across methods . The trace mode closely follows the contours of the non-ideal cell; however, irregularity of shape and contour of the non-ideal cell may be accentuated. Hand-tracing of the non-ideal cell tends to be dependent on the user’s assessment of where the true boundaries of the adipocyte exist.Analysis of adipocyte tissue in breast cancer surgical specimens has the potential to contribute to better understanding of host factors important in determining breast cancer outcomes. In addition to other factors such as BMI and macrophage infiltration, useful metabolic and inflammatory information can be gathered from an individual’s adipose histology, which can also be collected with routine breast biopsies during standard surgical pathology methods and are inexpensive to assay. Adipose tissue permits quantitative, morphological and visual analysis, which may reveal further insights into a patient’s overall risk factors. For example, adipocyte size distribution and macrophage infiltration  are assoThe primary objective of this work was to develop a new semi-automated method for adipocyte quantitation that demonstrates efficiency and accuracy of adipocyte quantification across multiple sample type, and is better than conventional methods. For the purposes of quantifying adipocytes to determine size distribution as a supplemental assessment of risk, speed and precision of analysis are both highly relevant and critically important. The secondary objective was to develop a full-service software tool for users to analyse a variety of adipocyte samples with the ability to choose different methods as needed. Results of testing show that the AdipoCyze tool was able to quantify adipocyte samples using a variety of quantification methods, including the ability to leverage multiple methods in a single analysis as shown in We compared the novel semi-automated trace mode (TM) method with the hand trace (HT) and ellipse approximation (EA) methods. We considered the HT method as the reference method throughout the analysis. As described above, a comparison of the semi-automated trace mode (TM) and emerging fully automated methods was not conducted here, as emerging methods are not considered standard laboratory practice.Precision of methods was assessed by measuring the variation in the quantification of cells over three repeated runs, as demonstrated in error bars in In order to compare the accuracy of the three methods of adipocyte quantification, we examined the difference between average measurements per cell number. Using the HT method as a reference , it appeThe leftward shift of adipocyte size distribution of the TM method relative to HT and EA is consistent with the finding that TM underestimates adipocyte size relative to HT. However, the general shape and features of the size distribution aligned across the methods. This analysis may benefit from a larger sample size to eliminate possible biases from a limited number of histogram bins. Concordance exists across methods, however results from the tracing algorithm demonstrated that HT and EA methods tend to over-estimate cell size relative to TM as suggested by the linear intercepts, while concordance between HT and TM appears to be strongest.Analysis rate and overall speed were important metrics for evaluation. The TM method demonstrated the fastest rate of analysis compared to the HT and EA methods. It is noteworthy that the TM rate of analysis poorly fits a linear regression, suggesting a non-linear equation. This can be explained by the additional time required at the beginning of the analysis to transform the image, while subsequent measurements are made very quickly. While it requires about double the amount of time to analyse the first cell using the TM method as HT and EA methods, the TM method completed the analysis in nearly half the time of the EA method and less than one-quarter of the time of the HT method.Results of comparing the three methods demonstrated that the semi-automated tracing algorithm improved speed, accuracy and precision compared to conventional methods, and preserved adipocyte size distribution. Our work demonstrates that the AdipoCyze tool offers a viable option to quantify adipocyte samples and improves overall efficiency, accuracy and precision, while providing flexibility to work with a wide range of histological sample types as shown in 2) and a calculation of a fitment factor to fit TM and HT measurements is warranted. Additional investigation and future development of this method, such as incorporating contemporary techniques of advanced computer vision, machine learning and artificial intelligence approaches, are needed to further enhance and automate adipocyte quantification. Additionally, combining adipocyte size distribution analysis with other clinical and non-clinical parameters, morphological features including crown-like structures, and other factors into a single platform may aid in more comprehensively understanding metabolic status for patients.AdipoCyze is the first adipocyte-specific image quantification platform to provide the investigator with multiple methods of quantifying adipocytes in a single analysis . WidesprThe population in which the tool was developed was comprised only African-American women, who had different degrees of obesity and metabolic health. Future validation studies must include other races and test the limits of the tool with a range of subject ages, and in different institutions where the patient population is heterogeneous. It is also possible that medications for Type 2 diabetes, such as metformin or glitazone combinations, which are commonly prescribed for U.S. patients to improve glucose control and adipogenesis, may change adipocyte sizes in ways that the tool can detect, but this prediction must be tested rigorously. Finally, adipocyte size distribution is related to metabolic health in tissues other than breast, such as subcutaneous, omental and visceral adipose depots, in both male and female subjects. A full range of adipose depots must be tested, including for the understudied cases of male breast cancer, a typically aggressive disease, where mechanisms of inflammation, adipocyte size distribution and tumour progression are unknown. Although we have focused here on applications to the microenvironment of women with breast cancer, we point out that AdipoCyze is a generic tool that can be used to quantify adipocyte size in any adipose tissue. Breast adipose tissue biopsies are not performed as the standard of care for metabolic assessment in women without breast cancer or suspected breast cancer. As the relationships between cardiometabolic risk, obesity and cancer outcomes are better understood, broader understanding of the size distribution and morphological characteristics of adipocytes in different adipose depots may prove to have diagnostic and prognostic value.Click here for additional data file.


Light detection and ranging (LiDAR) sensors help autonomous vehicles detect the surrounding environment and the exact distance to an object’s position. Conventional LiDAR sensors require a certain amount of power consumption because they detect objects by transmitting lasers at a regular interval according to a horizontal angular resolution (HAR). However, because the LiDAR sensors, which continuously consume power inefficiently, have a fatal effect on autonomous and electric vehicles using battery power, power consumption efficiency needs to be improved. In this paper, we propose algorithms to improve the inefficient power consumption of conventional LiDAR sensors, and efficiently reduce power consumption in two ways: (a) controlling the HAR to vary the laser transmission period ( With the rapid development of automotive technology, the types and quantities of sensors mounted on automobiles are gradually increasing, and the quantitative and qualitative improvement of sensors provides safety and convenience for drivers and passengers ,2,3. Thesor (t2) ,9,10,11.A LiDAR sensor, which detects the exact distance from an object by transmitting a laser, consists of a laser diode (LD), an avalanche photo diode (APD), a time-to-digital converter (TDC), and signal processing units, as shown in The LD transmits the laser, which is focused through a light transmitting lens. The laser transmitted from the LD is reflected back from the object and received by the APD through the light-receiving lens. The TDC measures the difference between the time the LD transmits the laser and the time the APD receives it, and then converts the difference to the ToF. The signal-processing unit, denoted by a microprocessor (MP), receives the ToF from the TDC and calculates the distance between the LiDAR sensor and the object.The laser of the LiDAR sensor can be classified into a pulsed, amplitude-modulated continuous-wave (AMCW), and frequency-modulated continuous-wave (FMCW) according to the transmission principle. The pulsed is a method of transmitting a laser with an instantaneous peak power using a short pulse of several nanoseconds. Because an intensity of an instantaneous laser is strong, it is used for long distance measurement. The AMCW is a method of transmitting a continuous laser. The distance is measured by comparing phases of the transmitted and backscattered detected waves. Because it measures a phase shift of the transmitted and received laser, it is not suitable for an accurate distance and long distance measurement . The FMCThe types of LiDAR sensors that measure distance are categorized into scanning sensors, microelectromechanical system (MEMS) sensors, flash sensors, and optical phased array (OPA) sensors. Scanning and MEMS sensors use mirrors to spread the laser to detect multiple directions. Scanning sensors use a mirror rotated by a motor to change the angle at which the laser is reflected and transmitted ,16. MEMSIn this paper, among the various types of LiDAR sensors, we use a scanning LiDAR sensor with a pulsed laser, which is best suited for autonomous vehicles requiring a wide field of view.This paper is organized as follows. As numerous high-tech devices are developed in various fields, miniaturization is pursued for convenience and portability. In addition, low-power issues are being discussed to enable the operation of small batteries for portability. To satisfy these requirements, the structure of the signal processing hardware has been modified in the past to reduce power consumption ,25. ReceRadio detection and ranging (RADAR) sensors, similar to LiDAR sensors, have been applied in various fields for a long time, but have recently been introduced in vehicles . As RADACurrently, the conventional LiDAR sensors on the market have the disadvantage of inefficient power consumption because of the constant operation of a vertical angular resolution (VAR) and horizontal angular resolution (HAR) fixed. In particular, because the fatal disadvantage of the LiDAR sensor causes vulnerabilities in autonomous vehicles equipped with multiple sensors and electric vehicles using batteries as a power source, it is necessary to improve the operation method to achieve efficient power consumption ,2. A solThe LiDAR sensor controls and changes the laser transmission period  motor, which rotates the mirror, and an encoder within the structure of the typical LiDAR sensor, as shown in The MP calculates the motor’s rotation angle using the angle data received from the encoder and controls the duty cycle of a pulse width modulation (PWM) signal with the motor driver. When the mirror’s angle is in the detection range, the MP triggers a START signal to the LD. The LD, which receives the START signal from the MP, transmits a STOP1 signal to the TDC at the same time as the laser transmission. The TDC that received the STOP1 signal from the LD counts using an internal timer (TMR) until STOP2 signals from each channel of the APD come in. Each channel of the APD receives the laser reflected by the object and sends the STOP2 signal to stop the TDC from counting. The TDC transmits its count values from the STOP1 signal to the multi-channel STOP2 signal and then to the MP. After receiving the count value from the TDC, the MP converts the distance value by applying the speed of light: When the MP sends the START signal to the LD and TDC, the TDC that receives the START signal waits for the STOP1 signal from the LD. The LD that received the START signal from the MP transmits the laser and sends a STOP1 signal to the TDC at the same time. When the laser reflected from the object reaches each channel of the APD, the STOP2 signals are transmitted to the TDC. The TDC’s TMR counts from the input time of the STOP1 signal until the STOP2 signal is received by each channel of the APD. When the TMR finishes counting because all channels received STOP2 signals, the TDC sends an interrupt signal, which is the signal that reception is complete for all channels, and the ToF data of each channel are transmitted to the MP using a serial peripheral interface (SPI) communication.The energy consumption of one pulsed laser pulse transmitted from LD, as denoted by Equation . The LD n cells. The total energy consumption of the APD’s n channels, as denoted by Each channel of the APD statically consumes power, as denoted by Equation .(2)EAPDThe TDC has an oscillator (OSC) that consumes power, as denoted by Equation .(3)ETDCThe operating power of SPI communication, which is implemented for faster communication at the hardware level and widely used for data transmission between sensors, is also consumed during such data communication. As shown in Equation , the eneWhen the MP receives data from the TDC via the SPI communication, the MP’s power consumption, as denoted by Equation . EP denoThe LiDAR sensor’s total energy consumption, as denoted by Equation .(6)ETotIf the LiDAR sensor, which periodically transmits the laser with the certain HAR, detects objects, it consumes a constant energy as much as In addition, if the HAR is decreased by widening In this paper, we propose methods to efficiently reduce the sensor’s power consumption by varying the HAR of the 16-channel scanning LiDAR sensor. The proposed LiDAR sensor is designed and manufactured for vehicles and has the specifications as shown in The LD of the proposed LiDAR sensor transmits a single-beam laser, which is the VFoV of 9.6Therefore, the proposed LiDAR sensor’s VAR is determined by the APD’s 16 sensing cells as 0.6As shown in As shown in With these specifications, we propose methods to efficiently reduce the power consumption of the LiDAR sensor from two perspectives: the vehicle’s speed and the sensor’s surrounding environment. In terms of the vehicle’s speed, the LiDAR sensor controls the HAR to reduce the dynamic power consumption. In terms of the sensor’s surroundings, the LiDAR sensor goes into sleep mode to minimize the static power consumption.A LiDAR sensor with the same HAR, Algorithm 1: Speed detection-based accuracy control.The LiDAR sensor does not need to detect the surroundings with high HAR when the vehicle is stopped or when objects are not detected at very long distances. Based on the environmental detection results, the MP reduces the power consumption by entering sleep mode, which commands the LiDAR sensor to sleep. As shown in Algorithm 2: Environment sensing-based accuracy control.The environment sensing-based LiDAR sensor reduces the power consumption in two cases: when the vehicle is moving or not moving. When the vehicle is driving, the LiDAR sensor operates based on the method represented in For an experiment with the proposed algorithm, we designed private hardware based on a Zynq7020 processor  and manufactured a LiDAR sensor module. To verify the LiDAR sensor, a test environment through the LiDAR sensor and viewer program was configured as shown in The experiment was divided into two types, and the simulation results of the produced chip are shown based on the experimental results. First, the resulting change in The following experiment results confirm the variation of Additionally, the LiDAR sensor’s HAR was varied by transmitting the laser every rotation, but in sleep mode, the laser was transmitted only once every five rotations to further reduce the power consumption in the environment sensing-based accuracy control mode. Previously, the output of In a red waveform of the normality section, an average current (AC) of 0.578 A and an average power consumption (APC) of 6.971 W were obtained using the LiDAR sensor’s power consumption in the no-load state without driving the LD. The blue waveform shows the APC of each from 7.442 W to 7.154 W, from As described above, the APC is reduced when varying In the sleep mode with The proposed LiDAR sensor’s algorithm clearly has a risk factor of four cycles (153.24 ms) that does not detect an object in sleep mode during the environmental-sensing control. This issue is considered to be negligible because it immediately switches to active mode when surrounding conditions change in sleep mode when the vehicle is stop. In the future, further work on an adaptive mode that immediately exits sleep mode when an event occurs through dynamic control of sleep mode in conjunction with other sensors  of the autonomous vehicle is needed.A designed chip was manufactured as shown in The chip is a MP with a built-in ARM Cortex-M3  that has 128 KB of program memory and 64 KB of data memory. In addition, we designed the chip to use external expansion memory in case the internal memory capacity is insufficient, which can be confirmed by the block diagram shown in This paper proposes an algorithm to improve the inefficient constant operation method of conventional LiDAR sensors. Conventional LiDAR sensors inefficiently consume the operating power because they do not consider the vehicle’s speed or the surrounding conditions. The proposed LiDAR sensor is implemented with software and hardware using the proposed algorithm to reduce the power consumption by varying the accuracy of a LiDAR sensor to be applied to electric and autonomous vehicles with limited power consumption. The proposed power-control algorithm operates according to two viewpoints: the vehicle’s speed and the surrounding environment. First, the LiDAR sensor controls the laser’s HAR based on the vehicle’s speed to reduce the dynamic power consumption. Second, when the surrounding environment does not change for a certain time period, the proposed LiDAR sensor reduces the static power consumption by minimizing unnecessary detection through sleep mode. When the HAR was operated at 55.52% of


Considering the ocean water’s optical attenuation is significantly larger than that of Fiber Channel, we propose an approach to enhance the security of underwater continuous-variable quantum key distribution (CVQKD). In particular, the photon subtraction operation is performed at the emitter to enhance quantum entanglement, thereby improving the underwater transmission performance of the CVQKD. Simulation results show that the photon subtraction operation can effectively improve the performance of CVQKD in terms of underwater transmission distance. We also compare the performance of the proposed protocol in different water qualities, which shows the advantage of our protocol against water deterioration. Therefore, we provide a suitable scheme for establishing secure communication between submarine and submarine vehicles. Quantum communication is a new type of communication method and quantum key distribution (QKD) ,2,3,4 isThe effective transmission distance of underwater CVQKD is significantly weaker than that of both fiber and air channels but it can be applied to the height safety areas. For example, underwater detection equipment can safely transmit information to an underwater platform . In thisThe purpose of this paper is to improve the performance of underwater CVQKD and analyze its performance based on the transmittance of seawater. At present, there have been many experiments to prove that apply photon subtraction operation can improve the entanglement between quantum, prolong the transmission distance of CVQKD protocols using two-mode squeezed vacuum (TMSV) states ,22,23,24This paper is organized as follows: In In this section, we describe the underwater CVQKD scheme with photon subtraction. We find that photon subtraction can enhance the entanglement of TMSV state, thereby improving CVQKD scheme. In addition, as a quantum information transmission medium, water has a large attenuation compared with fiber or atmosphere, therefore we consider the water transmittance of CVQKD scheme in what follows.A and B, where A is the annihilation operator, denoted as B is the creation operator, denoted as A and B exist in the equation V, whereThe CVQKD system with photon subtraction is depicted in A and B generated by TMSV, respectively. The mode B will be transformed into mode Alice performs heterodyne detection and photon subtraction operations on modes Since Alice can decide whether or not to approve or deny each data after Bob completes the measurement, the rejected data can be considered as the bait data to enhance the security of the former non-Gaussian protocol .B passes through the beam splitter with a transmittance of T to obtain modes A and On Alice’s side, the EB scheme of CVQKD via photon subtraction operation is shown in Alice perform heterodyne detection and Bob uses homodyne detection, which is convenient to implement in experimentation. Suppose In the CVQKD system, Alice uses the photon subtracted TMSV state as the source and she will perform heterodyne detection on mode A. As shown in r becomes larger as the depth D increases.When Alice and Bob exchange information, Alice and Bob are assumed to be peer-to-peer. In this case, the fact that light is scattered in the forward direction has a positive impact on underwater communication because it is the amount of such scattered light source that reaches the underwater receiver from the perspective of the link budget perspective. Obviously, both the model map and the photon intensity map show that the seawater can hugely influent photon’s transmission. Next, in view of the above phenomenon, we build a closed system where the dissipation is neglected, study the effect of photon subtraction operation on underwater CVQKD and give the derivation for calculating the transmittance of photons in seawater.Light travels harder in seawater than both fiber and atmospheric channels, since there are two processes affect light propagation in seawater, which called absorption and scattering respectively. Although we all know that photon transmission paths are straight lines, the transmission path of light can be changed especially in the seawater, as the photons many interact with certain particles. This phenomenon is called scattering. On the other side, photon energy loss caused by the interaction of photons and particles is called absorption, which is an irreversible thermal process. The superposition of the above process becomes a description of the beam attenuation coefficient D is the depth.Assuming that the underwater channel is a linear attenuation model. The transmittance of seawater can be calculated byIn this section, we first derive the secret key rate for underwater CVQKD protocol via photon subtraction. Then, the parameters involved in the secret key rate are estimated for the improvement of the underwater CVQKD system.After the quantum signal sent by Alice is received by Bob, the final covariance matrix between them can be described asAssuming that Alice and Bob perform heterodyne detection and homodyne detection respectively, the resulting secret key rate in reverse reconciliation scenario can be given byThe effect of the light in seawater can be described with absorption coefficient According to the above-mentioned analysis, 520 mm light is chosen to demonstrate the influence of propagation distance on the performance of the underwater CVQKD system via the non-Gaussian operation. The coefficient values k-photon subtraction operations, the probability of success can be determined by the transmittances T of T. The lines from top to bottom represent the probabilities of success for one-photon subtraction, two-photon subtraction, three-photon subtraction and four-photon subtraction, respectively. We find that as the number of photons increases, the probability of success decreases. The best of success probability is After Alice performs the k-photon subtraction operation, different water quality and different transmittance T of In this section, we simulate the secret key rate of underwater CVQKD via photon subtraction. The secret key rate of CVQKD is affected by various parameters when calculating. Therefore, in order to reflect the actual situation more realistically, we performed dynamic analysis on different parameters to obtain different secret key rate simulation results. It includes different The performance of CVQKD under pure seawater via photon subtraction are shown in T of the T range from 0–1 and different depth range from 0–140 m. When the transmission depth is short, the smaller the transmittance (T in transmission can extend the transmission distance while ensuring safe communication. Regardless of the one-photon subtraction operation or the two-photon subtraction operation, the performance situation is similar. However, since the success probability of two-photon subtraction operation is less than that of one-photon subtraction operation, the transmission distance of CVQKD via two-photon subtraction operation is outperformed by CVQKD via one-photon subtraction operation.In the photon subtraction operation, the transmittance We have suggested an improved underwater CVQKD by performing photon subtraction. In order to lengthen the transmission distance of the system, we deploy the photon subtraction-involved non-Gaussian operation in Alice’s operating procedures. We obtain the optimal absorption coefficient value under different seawater quality using the extensive data, although the probability of successful photon subtraction is affected by the transmittance of Alice’s BS. The simulation results show that the maximal transmission distance is remarkably increased after using photon subtraction. We also compare the performance of the proposed protocol in different water quality, which shows the advantage of our protocol against water deterioration. Moreover, the simulation parameters come from the reported experiments, which is very useful for our future research on building a global underwater secure communication network.