Approximately one third of cancer patients will develop spinal metastases, that can be associated with back pain, neurological symptoms and deterioration in performance status. Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) have been offered in clinical practice mainly for the management of oligometastatic and oligoprogressive patients, allowing the prescription of high total dose delivered in one or few sessions to small target volumes, minimizing the dose exposure of normal tissues. Due to the high delivered doses and the proximity of critical organs at risk (OAR) such as the spinal cord, the correct definition of the treatment volume becomes even more important in SBRT treatment, thus making it necessary to standardize the method of target definition and contouring, through the adoption of specific guidelines and specific automatic contouring tools. An automatic target contouring system for spine SBRT is useful to reduce inter-observer differences in target definition. In this study, an automatic contouring tool was evaluated.Simulation CT scans and MRI data of 20 patients with spinal metastases were evaluated. To evaluate the advantage of the automatic target contouring tool (Elements SmartBrush Spine), which uses the identification of different densities within the target vertebra, we evaluated the agreement of the contours of 20 spinal target , outlined by three independent observers using the automatic tool compared to the contours obtained manually, and measured by DICE similarity coefficient.p = 0.048).The agreement of GTV contours outlined by independent operators was superior with the use of the automatic contour tool compared to manually outlined contours (mean DICE coefficient 0.75 vs 0.57, The dedicated contouring tool allows greater precision and reduction of inter-observer differences in the delineation of the target in SBRT spines. Thus, the evaluated system could be useful in the setting of spinal SBRT to reduce uncertainties of contouring increasing the level of precision on target delivered doses. SmartBrush tool is represented by the identification of different density grey levels, which can decrease the inter-observer differences in target definition. The aim of the present study is to assess the SmartBrush impact in patients with spinal metastases, eligible for SBRT.Local back pain and neurological symptoms are the most common clinical disease presentations in spinal metastases . TraditiSmartBrush software  in patients with spinal metastases. Specifically, 20 spinal lesions eligible for SBRT treatments were included in the study. In all cases, 20 target volumes were equally visible and delineable both in CT scans (as osteolytic or thickening areas) and in MRI scans. All the procedures have been described in a previous publication [In the current study, we analyzed the impact of the lication . BrieflyFor MRI scans, a T2-weighted sequence was rigidly registered with the simulation CT scan for a refined definition of healthy structures such as spinal cord, sacral plexus or cauda equina. The organs at risk (OARs), depending on tumor site, were automatically delineated by the software based on an anatomical atlas.For baseline treatment, the gross tumor volume (GTV) was defined as the macroscopic contrast-enhancing lesion detected on diagnostic imaging; Smartbrush software allows an easier recognition of the affected region with a direct adjustment for CTV refined definition. No GTV manual refinement is performed. The clinical target volume (CTV) was automatically generated by the software according to international guidelines and automatically labeled to avoid vertebral crossing . AfterwaTo evaluate the impact of the automatic target contouring tool (SmartBrush), which uses the identification of different densities within the target vertebra, we evaluated the agreement of the contours of GTV of 20 spinal targets  outlined by three independent observers experienced in spine SBRT treatments, using the automatic tool compared to the contours obtained manually and measured by DICE similarity coefficient.Given the different contouring by independent observers as A and B, the Dice coefficient is defined as:dic ≤ 1).The Dice coefficient represents the ratio of overlapped region between different contoured target volumes .Data from 20 patients treated for spine metastases were extracted for the purpose of the present analysis. More specifically, 2 were cervical targets, 9 thoracic and 9 were located in the lumbar spine. A median prescription dose of 24 Gy was delivered in 3 fractions using image-guided volumetric modulated arc therapy by means of a TrueBeam linear accelerator . A simultaneous integrated boost to the GTV was delivered for a median prescription dose of 27 Gy in 3 fractions.Median GTV volume was 1.44 cc , median CTV volume was 22.1 cc . Examples of target volume delineation are displayed in Fig. p = 0.048) with the use of the automatic contour tool (SmartBrush), that registered a mean DICE coefficient of 0.75  compared to manually outlined contours, that registered a mean DICE coefficient of 0.57 , Fig. The agreement of GTV contours outlined by three independent operators was statistically superior  of a dedicated software  for spinal metastases SBRT. We evaluated the accuracy of this novel specific contouring tool -SmartBrush- applied to retrospective simulation CT clinically acquired in 20 patients treated with Spine SBRT.To evaluate the advantage of using an automatic contouring tool (SmartBrush) based on the recognition of areas of different density within the target vertebra, we evaluated the concordance of the contours obtained by three independent observers with and without the use of the SmartBrush tool.The results showed a statistically greater agreement in the use of the contouring tool analyzed, compared to the manual delineation of the contours, allowing for greater homogeneity in the definition of the target.This last aspect is more relevant in the accurate definition of the GTV volumes, especially in view of the possibility of performing treatments with simultaneous integrated boost on the lesion evident in PET or MRI, within the vertebral target, to potentially increase local disease control.To date, few experiences in the literature report on the use of softwares for automatic segmentation of the target in radiotherapy. Hearn et al. have recently published the results of a comparison study between manual segmentation and semi-automated delineation of prostate GTV based on quantitative thresholding of intraprostatic apparent diffusion coefficient (ADC) and PET standardized uptake values (SUV), recording a significantly higher inter-observer agreement with the use of PET compared to MRI-based semiautomatic segmentation .Autosegmentation tools are an attractive option for clinicians, since they are supposed to facilitate everyday clinical practice, by reducing inter-observer variability and potentially reducing contouring time. Nonetheless, the role of the physician still remains irreplaceable. This is also confirmed by Meillan et al.  in a comA recent review by Francolini et al.  collecteFurther steps forward are awaited from the implementation of deep learning frameworks and artificial intelligence in daily clinical activity, for which some preliminary experiences have been recently published –25, suppSeveral advantages might be provided by the introduction of artificial intelligence systems, as machine-learning based networks are supposed to ease the radiation treatment planning procedure in all its phases. The contouring process might be improved both in terms of time-consumption issues and inter-observer variability, as already reported .This study has some limitations; first of all, the small sample size may affect the statistical power of our analysis. Nonetheless, we included three different physicians to better estimate the potential inter-observer variations: the main aim of the present study was to assess the impact of Smartbrush software compared to manual contouring in order to reduce inter-observer variability,A further analysis with a larger sample, other metrics tools, and the assessment of time consumption issues is currently ongoing at our Department.Moreover, in the specific setting of spinal metastases SBRT, to the best of our knowledge, the use of automated software for treatment planning and target contouring was previously investigated only in our preliminary institutional experience , supportLong term follow-up data are warranted to further assess the favorable impact of this technology from a clinical perspective in terms of both toxicity and clinical outcomes.The Elements® Spine SRS dedicated software for linac-based spinal SBRT treatment is a useful approach for patients with spinal metastases, improved by a dedicated automatic contouring tool (SmartBrush) that allows greater precision and reduction of inter-observer differences in the delineation of the target in SBRT spines.


Objectives: The aim of this study was to identify, compare and evaluate regulatory requirements for the biosimilar development and review processes in BRICS-TM  countries with mature regulatory systems of Australia, Canada, Singapore and Switzerland. It is hoped that this benchmark study provides an opportunity for BRICS-TM agencies to identify the key areas for improvement in their regulatory processes.Materials and Methods: A semi-quantitative questionnaire was developed covering the different criteria used in biosimilar development and registration process. Eleven regulatory agencies from BRICS-TM and ACSS  countries were invited to take part in this study. Data processing and analysis was carried out using descriptive statistics for quantitative data and content analysis to generate themes for qualitative data.Results and Discussions: Nine of the 11 regulatory agencies recruited for the study completed the questionnaire. China and Singapore did not meet the deadline due to lack of resources. The organisational structure of BRICS-TM agencies revealed support from external assessors by most of these agencies in comparison with ACSS agencies. There was absence of reliance approach and participation in harmonisation activities across most BRICS-TM agencies. Despite alignment over biosimilarity, the mandate for in vivo non-clinical studies and additional local clinical studies in some of the BRICS-TM countries illustrates a lack of effective implementation of a step-wise approach. Adopting flexible regulatory standards in the sourcing of a RBP (Reference Biologic Product) by BRICS-TM similar to ACSS, will facilitate cost-effective development of biosimilar products.Conclusions: Comparative assessment of the biosimilar regulatory framework of BRICS-TM with ACSS agencies reveals the scope for enhancing efficiency of the regulatory approval process. To achieve this, BRICS-TM agencies should consider relying on reference agencies for alternative review mechanisms such as abridged or verification models, streamlined processes for providing scientific advice to developers and for waiving local clinical studies in-lieu of advanced scientific data. Developing economies account for one-third of global growth in drug demand, with an overall annual growth rate of 5–8% . The BRIOpportunities exist for biosimilars in the emerging economies , due to Studies have been performed to compare the South African Health Products Regulatory Authority , TurkishThe aim of this study therefore was to identify, compare and evaluate the biosimilar regulatory strategy of BRICS-TM agencies with that of Australia, Canada, Singapore and Switzerland (ACSS Consortium), in an effort to identify and replicate best practices in biosimilar development and their authorisation processes.• Identify regulatory framework of the ACSS agencies:- identify resources of the agencies in the biosimilar domain,- identify biosimilar development criteria i.e., biosimilarity principle, comparative studies including physicochemical characterisation, non-clinical and clinical studies,- identify the biosimilar marketing authorisation approval pathway specifically for key milestones, validation time, queuing time, backlogs, requirement for sample analysis, conduct of GMP inspections, issuance of Public Assessment Reports (PARs), scientific guidance meetings and clinical trial mandates.• Identify challenges and areas for improvement.The objectives of this study were to:A semi-quantitative questionnaire was developed for the BRICS-TM agencies based on an already established questionnaire developed by the Centre for Innovation in Regulatory Science (CIRS)  and relePart I - Organisation of the agency - This part of the BDEA questionnaire consist of current agency structure, resources in the biosimilar domain and types of regulatory review models  employed for scientific assessment, level of data required, and extent of data assessment of the data including reliance on other authorities, if applicable. The rationale for including this section was to assess the capacity, strengths and weaknesses.Part II – Agency’s guidelines/views on biosimilar development criteria - This part includes questions related to biosimilarity principle, selection of RBP, comprehensive comparability criteria including physico-chemical, non-clinical and clinical studies and “must submit” documents that are required for a biosimilar marketing authorisation application. The rationale for inclusion of this section was to determine the extent of the regulatory requirements for biosimilar development and approval.Part III – Marketing authorisation approval pathway - This part covers questions with regards to key milestones i.e, the assessment process starting from receipt of the dossier, validation/screening, the number of cycles of scientific assessments including the questions to the sponsor/applicant, expert registration committee meetings to the final decision on approval or rejection of a biosimilar for registration. A standardised process map, developed based on the experience of studying established and emerging regulatory authorities, was embedded in the questionnaire. The rationale for inclusion of this section was to evaluate different stages of the review process and timelines for each milestone.The content validity of the BDEA including its relevance was carried out by a medium sized independent regulatory agency, the Regulatory Authority of Medicines, Equipment and Medical Device (CECMED), Cuba. Post validation, the questionnaire was further concised by removal of duplication of questions and restructured to make a 35-page long questionnaire. The BDEA consists of three parts:Eleven regulatory agencies from BRICS-TM and ACSS countries were invited to take part in this comparative study. The study protocol was shared with the 11 agencies together with the electronic self-administered BDEA questionnaire and the supporting instruction for completion. The data collection took place between August to November 2020. The potential study participants were identified via each respective agency’s general email addresses obtained from agency websites, LinkedIn, the research team’s personal contacts, ex-employee and local leading regulatory consultants for each authority. They were selected based on their work experience in the biologic or biosimilar division of the authority, having held a position as a general manager or above (senior management) or a leading regulatory consultant with a close working relationship with the relevant authority in the biosimilar domain. They were sent an electronic mail with brief information about project and the questionnaire, the objective of the study, the number of authorities to be included and requesting their agreement to participate in the study. The questionnaire was completed by a member of the biologic team and approved by the section head. This was followed up by a face-to-face or virtual meetings after receipt of the completed questionnaire with each agency of the BRICS-TM and ACSS countries. Such meetings were arranged to verify the validity of the responses to the questionnaire. Also, copies of the relevant guidelines were requested as part of the questionnaire to verify the responses and to correlate the actual regulatory requirements. In addition, data received from the agency pertaining to number of applications received and reviewed by agencies in reference (ACSS) and test (BRICS-TM) group were assessed.The therapeutics product branch of HSA (Singapore) was unable to participate due to stretched resources and higher priorities in other areas due to the COVID-19 pandemic. The second-best option of approaching leading regulatory consultant in Singapore was used. However, the participant was unable to provide the necessary information due to lack of time and difficulty in obtaining clarity from HSA on certain areas of the questionnaire.Data processing and analysis were carried out using Microsoft Excel. The questionnaire (BDEA) is a mixture of qualitative and quantitative questions. Therefore, both quantitative and qualitative analyses were carried out. The descriptive statistics were applied to the quantitative questions of the questionnaire. The analysis for qualitative data was carried out using content analysis and inductive coding in order to generate themes and subthemes .The study has been approved by the Health, Science, Engineering and Technology ECDA, University of Hertfordshire [Reference Protocol number: aLMS/PGR/UH/03332 (1)].Part I – Organisation of the agency;Part II – Biosimilar development criteria; andPart III – Marketing authorisation process.For the purpose of better clarity, the results will be presented in three parts:Out of 11 regulatory agencies , four BRICS-TM  and three ACSS  agencies agreed to participate in the study. Since access to two agencies, the Federal Commission for the Protection Against Sanitary Risks (COFEPRIS), Mexico and the Russian Ministry of Health were experiencing resource constraints, a leading regulatory consultant, experienced in working closely with these agencies and having biosimilar expertise was recruited in each country. The respondents from the consulting firms were either the Chief Executive Officer or equivalent. The consultants used for Mexico and Russia were closely associated with the respective agencies regarding registration of biosimilar products, engaged with the agencies for reviewing clinical study protocols and acting as external assessors for the agency relating to biosimilar products. National Medical Product Administration (NMPA), China and Health Science Agency (HSA), Singapore were not able to complete questionnaire on time, due to lack of resources.TGA  - Though the agency did not have an established dedicated biologic division, the strength of the assigned biologic staff was 3.7% of the total. In addition to qualified internal assessors with B.Sc. to PhD degrees, external evaluators were engaged for the review of clinical data. Of the three review models, “Type II- (Abridged)” and “Type III – (Full review)” of marketing authorisation applications assessments were frequently carried out by the TGA .BRDD (Canada) - The strength of the biological division within the agency was 2.08% in comparison with the total staff of the agency. The agency restricted use of external assessors and had qualified biological assessors with B.Sc. to PhD degrees. The marketing authorisation applications were reviewed using “Type III - Full review” model with little or no scope for relying on “Type I (Verification)” or “Type II (Abridged review)” models . InsteadSwissmedic (Switzerland) - There is no distinct biological division within the agency and hence, with the exception of CMC reviewers, there were common reviewers for reviewing both biologic and non-biologic applications. The minimum qualification of the internal assessors was PhD, PharmD or MD degree. The agency relied on “Type I (Verification)” and “Type III (Full review)” models for biosimilar marketing authorisation applications data assessment.Comparison of BRICS-TM With ACSS - The strength of biosimilar assessors across BRICS-TM and ACSS was between 1 and 5%, reflecting no large variance in nine agencies resources. Most of the BRICS-TM agencies (except ANVISA and Russia MoH) appointed external assessors to review CMC, non-clinical and clinical data, as compared to ACSS agencies. The ACSS agencies followed the “Type III” model for the majority of the applications and have flexibilities to follow “Type I” (Swissmedic) and “Type II” (TGA) as well. In addition, these four national regulatory agencies have formed the ACSS consortium in 2007 with the objective of enhancing the effectiveness and efficiency of their regulatory systems . Some ofin vitro non-clinical PK/PD studies and literature-based clinical performance evaluation, additional in vivo safety data plus confirmatory clinical safety and efficacy trials. The TGA, BRDD and Swissmedic accepted clinical data for the Phase III  study from reference countries and do not mandate applicant to carry out clinical trials in the local population.The ACSS agencies expected the sponsor to demonstrate biosimilarity of the proposed biosimilar product with its reference product by proving satisfactory physicochemical and biological characterisation with Further, interchangeability is not regulated by law in Switzerland, allowing the prescriber to decide on switching based on patients needs. In the case of TGA, interchangeability policy is under the jurisdiction of the Department of Health and funded through the Pharmaceutical Benefits Scheme. The pharmacists of each province in Canada are charged with the authority to declare two products interchangeable according to its own rules and regulations, without the intervention of the prescriber.The biosimilarity principles of BRICS-TM agencies are aligned with the expectations of ACSS in terms of different types of studies. The interchangeability decision in BRICS-TM countries lies with the prescriber, except in Russia (where it is regulated by the agency), whereas ACSS follows varied paths. The major challenge with a few of the BRICS-TM agencies is that they require the clinical studies to be conducted locally , i.e., tThe TGA, BRDD and Swissmedic mandated locally authorised reference products  that have been marketed for substantial periods of time in their country. They also allowed applicants to use non-locally authorised reference products as part of the development, in the absence of a locally approved reference product. The TGA and Swissmedic accepted use or sourcing of EU or US licensed reference products, whereas BRDD additionally accepted United Kingdom licensed reference products. The evidence of bridging studies to prove sameness of a foreign reference product with the reference product authorised in respective countries was an essential part of the submission for applications to TGA and BRDD. While both agencies required multiple lots of RBP with varied shelf-life for comparability studies, they did not allow change in the reference product during development and comparability studies. The most notable difference was observed with Swissmedic where the requirement for bridging studies had been removed.While ACSS agencies are flexible for using non-locally authorised reference products, ANVISA and Russia MoH prefer to have locally authorised reference products as part of the development. Although silence on bridging studies  by each The TGA, BRDD and Swissmedic followed ICH Q6B  for settThe BRICS-TM and ACSS agencies were broadly aligned on this parameter as mentioned in the WHO guidelines , except The TGA recognised the limitations of the biosimilar applicants in matching the age of the proposed biosimilar products with the innovator product and hence did not mandate these studies as part of the application. Swissmedic accepted comparative stability studies as supportive data while BRDD required it as part of the application.In general, comparability study expectations of BRICS-TM regulatory agencies were similar to those required by the ACSS countries.in vivo toxicity studies if comparability between the biosimilar and the reference product had been sufficiently addressed by in vitro studies based on availability of relevant animal models. Swissmedic followed EMEA/CHMP/BMWP/42832/2005 Rev1  letter of submission during evaluation of the protocol existed with Swissmedic. Prior to initiating a clinical trial or implementing an amendment to a clinical trial at a site, BRDD requires the proposed trial protocol and Informed Consent Form (ICF) to be reviewed and approved by a Research Ethics Committee (REC) as defined in the regulations. The TGA does not provide any clarity on the CTA approval process or timelines. Both ACSS and BRICS-TM countries require an Ethical Committee letter submitted during clinical trials.The Certificate of Pharmaceutical Product (CPP) in the technical dossier is not required as part of the application by ACSS agencies. The validation of the application and target time to request additional data is in place as one of the milestones. The current queue time with BRDD is 300 calendar days whereas such information was unavailable for the TGA and Swissmedic. External experts for clinical opinion were contractually engaged by the TGA and Swissmedic. The deficiencies in the dossier were presented to the applicant in one single lot from all different sections of the dossier. Sample analysis was performed as part of the market release post approval of the product, in Australia and Switzerland. The GMP inspection is mandated by all the ACSS agencies. For TGA, the GMP inspection could be either on-site or document-based verification and the inspection is conducted concurrently along with the assessment of the product dossier. However, Swissmedic accepted document-based verification for GMP certification of the manufacturing site. The BRDD relies on on-site evaluation for certifying the manufacturer for process and own inspection or pursuant to MOU’s for GMP purposes . The on-The BRICS-TM agencies (except TITCK) were yet to implement a GMP verification process through off-site review of documents based on a reference agency approval. TITCK issue GMP certificate after paper-based evaluation of the GMP submission.Public assessment reports are issued by TGA, Australia (AusPAR) and BRDD, Canada for biosimilar products. Currently, PAR from Swissmedic (SwissPAR) is issued only for new active substances and is available upon request for biosimilars. However, among the BRICS-TM countries, only ANVISA publishes equivalent document on their website. Publication of PARs by ACSS agencies thus ensures transparency, by providing access to information by pharmaceutical industry, other health authorities, healthcare professionals and patients , on the A flow chart on the dossier review and approval pathway is illustrated in Biosimilars offer patients in the emerging economies the opportunity to receive key biologic therapies that would otherwise be denied to them due to costs and, therefore, they offer a great growth potential in such economies. However, optimal access to biosimilars depends on collaboration between the relevant stakeholders including policy-makers, regulators, physicians and the industry. In this context, the most important role is played by the regulatory authorities as they provide the regulatory oversight of biosimilars throughout their product life-cycle to ensure only high-quality, safe and effective biosimilars are available in the market . HoweverComparison of regulatory systems from different countries is one of the methods to gain insights on the limitations of regulatory processes, and thereby to overcome some of these challenges. This study of the guidelines and processes for biosimilar development and authorisation by regulatory agencies in BRICS-TM countries in comparison with the ACSS consortium presents various opportunities to build efficiencies in their respective regulatory frameworks.Although the organisation is contextual and country-specific often based on country’s legal system, the results for the ACSS countries showed a great similarity . In terms of regulatory requirements being non-contextual, the results confirmed this notion by showing a large degree of similarity. It could be postulated that we could have simply used the acceptable international best practices for purpose of comparison, however, given the dynamic nature of biosimilar development and its expansion, it was envisaged that prospective up-to-date data collection would provide more accurate head-to-head comparison.in vivo non-clinical studies and repetition of confirmatory clinical trials in the local population is required  (Provision of pre-submission advice and scientific advisory meetings during the biosimilar development and application process to reduce time and costs. Scientific advice (SA) allows early communication between the companies and the regulators. With SA, companies can seek the regulator's opinion on quality, nonclinical, and various clinical aspects  of drug development . Seekingon (MAA) . By foston (MAA) . Allowinon (MAA) .The BRICS-TM agencies might have to consider flexibility for using non-authorised reference product from other emerging countries and reference agencies to simplify RBP sourcing. The sourcing of product batches of different ages from different markets for development purposes may present significant difficulties and incur costs . In 2009Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by the regulatory authorities as conditions of approval . It estaThe World Health Organisation (WHO) Certification Scheme was initially implemented to accelerate the availability of new drugs in developing countries by providing evidence of the quality of products through the use of the Certificate of Pharmaceutical Product (CPP) . HoweverThe BRICS-TM agencies should consider acceptance of off-site GMP audit in the GMP accreditation process to reduce delays caused by physical GMP inspections. For instance, the Pharmaceutical Inspection Co-operation Scheme (PIC/S)  aims at Like the ACSS agencies, the emerging economies of BRICS-TM need to move towards reliance and collaboration with other regulatory agencies. A shared or joint review approach for the assessment of dossier in the marketing authorisation application with other comparable agencies and a verification review for products that have been approved by two or more reference agencies and an abridged review for medicines approved by one or more agencies, with a full review only employed for those products that have not been reviewed elsewhere by a reference agency can be considered for reviewing of the product dossier. The World Health Organisation (WHO) supports the implementation of reliance on other regulators work as a general principle in order to make the best use of available resources and expertise. This principle enables leveraging the output of others whenever possible while placing a greater focus at the national level on value added regulatory activities that cannot be undertaken by other authorities, such as, but not limited to, in-country vigilance and market surveillance and control activities and oversight of local manufacturing and distribution. Reliance approaches facilitate timely access to safe, effective and quality-assured medical products and can help in regulatory preparedness and response, particularly during public health emergencies .


Prognostics and health management (PHM) with failure prognosis and maintenance decision-making as the core is an advanced technology to improve the safety, reliability, and operational economy of engineering systems. However, studies of failure prognosis and maintenance decision-making have been conducted separately over the past years. Key challenges remain open when the joint problem is considered. The aim of this paper is to develop an integrated strategy for dynamic predictive maintenance scheduling (DPMS) based on a deep auto-encoder and deep forest-assisted failure prognosis method. The proposed DPMS method involves a complete process from performing failure prognosis to making maintenance decisions. The first step is to extract representative features reflecting system degradation from raw sensor data by using a deep auto-encoder. Then, the features are fed into the deep forest to compute the failure probabilities in moving time horizons. Finally, an optimal maintenance-related decision is made through quickly evaluating the costs of different decisions with the failure probabilities. Verification was accomplished using NASA’s open datasets of aircraft engines, and the experimental results show that the proposed DPMS method outperforms several state-of-the-art methods, which can benefit precise maintenance decisions and reduce maintenance costs. The rapid development of industrial Internet of Things technology greatly promotes the complexity, integration, and intelligence of modern engineering systems ,2,3,4,5.In recent decades, failure prognosis has received extensive attention, and many research results have been achieved. For instance, an integrated feature-based failure prognosis method was developed in , where tHowever, the above studies only focused on the accuracy of failure prognosis and took no consideration on how to use these valuable failure prognostic results for maintenance decisions. Indeed, there are obvious advantages to jointly considering the two aspects of failure prognosis and maintenance decision-making. For example, in practice, the failure prognosis and maintenance decision-making can be regarded as a whole process affecting the safe operation of the system, where the accuracy of failure prognostics directly affects the effectiveness of maintenance decision-making. Accordingly, their joint research can provide important technical support for the integration of the control, decision-making, and management of complex engineering systems. For such a purpose, this paper develops a deep auto-encoder and deep forest-assisted failure prognosis method for dynamic predictive maintenance scheduling (DPMS). The proposed DPMS method involves a complete process from performing failure prognosis to making maintenance decisions. Firstly, representative features that can reflect system degradation are extracted from raw data by using a deep auto-encoder. Secondly, the features are processed by a deep forest network to compute the system failure probabilities in moving time horizons. Finally, these failure probabilities are used to compute the costs of possible maintenance decisions, and the maintenance activities are scheduled accordingly based on two rules.A unified and powerful deep auto-encoder and deep forest integrated algorithm is proposed to handle the raw condition monitoring data. It can automatically extract the representative features reflecting system degradation and construct the mapping between the features and discrete degradation states for failure prognosis.Two decision rules are designed to deal with the DPMS. With the prognostic failure probabilities, the maintenance and inventory decisions can be made through quickly evaluating the costs of different decisions.With NASA’s open datasets of aircraft engines, the proposed DPMS method outperforms several state-of-the-art methods, which can benefit precise maintenance decisions and reduce maintenance costs.The main contributions of this paper are highlighted as follows:The remainder of this paper is structured as follows. In The proposed methodology is based on real-time condition monitoring data  collected by multiple sensors installed in the system. It contains two parts, failure prognosis and maintenance decision-making, and the complete process from performing failure prognosis to making maintenance decisions is shown in In the failure prognosis stage, the use of a deep auto-encoder is proposed to extract the representative features reflecting system degradation from sensor data. Once the representative features are obtained, the mapping between features and degradation states can be constructed by using the deep forest algorithm, where the degradation states are determined according to the requirements of operational planners. As an illustration, if the operational planners require the failure information in two different time windows , without the need to set the number of forest layers in advance. Each layer of forest usually receives the feature vector generated from the previous layer, and then outputs the generated feature vector to the next layer. In the construction of each layer of the model, two kinds of random forests are contained, i.e., complete random forest (noted as random forest A) and ordinary random forest (noted as random forest B). The complete random forests consist of multiple decision trees, and each tree contains all the features. A feature is randomly selected as the split node of the split tree, and the splitting process is not terminated until each leaf node contains only one category or no more than 10 samples. The ordinary random forests randomly select The schematic diagram of the deep forest prognosis model constructed in this paper is shown in ni index  to selecGiven a sample set According to the optimal segmentation feature value h-th inspection period for example). For an option to order the spare part, the cost is computed byInventory decision: The inventory decision aims to determine whether to place a spare part order at the current inspection time . The representative features reflecting system degradation were extracted from raw sensor data by using a deep auto-encoder, while the inclusion of the deep auto-encoder allowed the nonlinear relationship between the representative features and discrete degradation states to be learned. The integration of these two models led to an effective failure prognosis model. With the prognostic failure probabilities, the maintenance and inventory activities are scheduled through quickly evaluating the costs of different decisions. The verification results using NASA’s open datasets of aircraft engines reveal the feasibility of the proposed DPMS method. According to the prognostic accuracies and average maintenance cost rates, the proposed method is better than several state-of-the-art methods. Future work will focus on the investigation of predictive maintenance strategy for more sophisticated systems with multiple components.


Electric and magneticfields have enabled both technological applicationsand fundamental discoveries in the areas of bottom-up material synthesis,dynamic phase transitions, and biophysics of living matter. Electricand magnetic fields are versatile external sources of energy thatpower the assembly and self-propulsion of colloidal particles. Inthis Invited Feature Article, we classify the mechanisms by whichexternal fields impact the structure and dynamics in colloidal dispersionsand augment their nonequilibrium behavior. The paper is purposelyintended to highlight the similarities between electrically and magneticallyactuated phenomena, providing a brief treatment of the origin of thetwo fields to understand the intrinsic analogies and differences.We survey the progress made in the static and dynamic assembly ofcolloids and the self-propulsion of active particles. Recent reportsof assembly-driven propulsion and propulsion-driven assembly haveblurred the conceptual boundaries and suggest an evolution in theresearch of nonequilibrium colloidal materials. We highlight the emergenceof colloids powered by external fields as model systems to understandliving matter and provide a perspective on future challenges in thearea of field-induced colloidal phenomena. Widespread knowledge of colloids in static equilibrium isthe reason for their ubiquity in everyday products and their use asmodel systems in studying the phase behavior of soft condensed matter.Recently, interest has shifted toward dynamic, out-of-equilibriumprocesses because of the potential in pushing the boundaries of materialsdesign based on the properties of the colloidal building blocks. Bothacademics and technologists are involved in the hunt for the principlesto program autonomous assembly and propulsion to actuate nonequilibriumprocesses. Nature builds, functionalizes, and animates objects atall scales, with unparalleled efficiency and versatility. It doesso by relying not solely on elemental variety but also on mechanismsthat dissipate external energy to move parts and assemble them intoliving matter.6 The definitions of these termshave evolved in the literature8 and are critical to this review; they are summarized below:(a)dissipative: operationsthat consume external energy to transition a system from an initialthermodynamic state to new states that can be in dynamic nonequilibriumor in a static kinetic trap(b)driven: type of dissipativecolloidal mechanism in which the structuring and motion of particlesare directed by the global energy gradient(c)active: type of dissipativecolloidal mechanism in which the structuring and motion are governedby energy gradients local to the particles(d)static assembly:assembly mechanism in which the final structure is maintained irrespectiveof the external energy source(e)dynamic assembly:assembly mechanism forming structures that rely on transient fieldcharacteristics such as strength and frequency(f)passive motion: migrationof particles across a global gradient in fieldThe versatility of electric and magnetic fields isdue to the abilityto power nonequilibrium dissipative phenomena which can be definedas driven or active.One of the most useful conceptual analogies of external field-inducedcolloidal phenomena is that of living systems, which have evolvedto use biochemical energy sources for the processes of life. Externalfields act as the energy source for synthetic particles to performtasks that potentially resemble life. Electrical impulses and magneticdomains provide a set of preprogrammable interactions that are tunablein small spaces and short times. Thus, colloids that would otherwisereach some thermodynamic equilibrium are instead compelled to formstructures and move in their environment in a nonequilibrium fashion.The interactions induced by electric and magnetic fields play a crucialrole in endowing colloids with “lifelike” features thatbridge the gap between natural and man-made materials 1. Living17 As will be further discussed below, the use of external electricand magnetic fields often requires the presence of an electricallyconductive or magnetic domain.18 Depositingthin patches of metal on the surface of particles is one of the mostcommon ways for experimentalists to introduce such domains in colloidalsystems.20 These patchy particles are most often polymeror silica microspheres with thin layers (∼101 nm)of metal such as gold, iron, or nickel deposited on selected areasto form patches on the surface. Many configurations can be obtainedusing methods such as glancing angle vapor deposition,19 with the most common being the Janus particlefirst proposed by de Gennes.21 This isa particle with a patch covering half of its surface resulting intwo hemispheres having different physical and/or chemical properties,reminiscent of the two-faced god of Roman mythology from which itborrows the name.Research in colloidalassembly and propulsion has greatly benefitedfrom the recent progress in the synthesis and fabrication of particleswith reduced symmetry.Exposing colloids to electric and magneticfields was once considereda loose intersection between the study of particle suspensions andelectromagnetism. It has now acquired its own standing within theresearch area of soft matter. This Article aims to highlight boththe unique features of using these external fields to assemble andpropel colloids as well as the variety of outcomes that ensue. Theprinciple underlined throughout the Article is the role of electricand magnetic fields in tuning the energy landscape of particles. Aholistic view of the research in the field of electrically and magneticallypowered soft matter is provided in Electric and magnetic fields morph theinteraction energy landscapeof particles that are susceptible to polarization. They are describedby vector fields as the magnitude and direction of both electric andmagnetic interactions vary in space. At colloidal length-scales, electricand magnetic fields are analogous in their effect of “polarizing”objects, i.e., inducing the formation of an effective dipole withinparticles. Such electric and magnetic dipoles interact in a highlydirectional fashion that is simultaneously attractive and repulsive,depending on the relative position of the particles and the fieldvector. The two fields are inherently coupled to give rise to theelectromagnetic force where the electric and magnetic components originate,respectively, from stationary and moving charges. In the context ofcolloid science, the electric and magnetic interactions have fundamentallydifferent origins with some consequences that affect their applicationin controlling colloidal assembly and propulsion.22 On the other hand, the ions in the outer layer, i.e., the diffuselayer, are dislocated when subjected to an external alternating current(ac) electric field  and thekinetic energy of moving particles . This versatility finds use in interchangeablyexploiting external energy for assembling and microstructuring devices,or moving objects in complex trajectories, with inherent advantagesfor biomedical and microrobotic applications.Magneticfields differ in their applicability from electric fields.They are applied in a contactless way and are chemically nonintrusive,especially at the field strengths required to manipulate colloids.The main limitation in using external magnetic fields is the rangeof materials that can be controlled. These must be magnetic or containa magnetic domain embedded in them to be susceptible to the magneticfield.pe, or a magnetic point-dipole, pm, expressed by26R is the radius ofthe particle, and εf and μf are,respectively, the electrical permittivity and the magnetic permeabilityof the medium. E and H are the vectors of the electric and magnetic fields, respectively. K represents the real part of the Clausius–Mossottifunction which provides a measure of the degree of polarization ofa particle. This is based on a contrast of electric permittivity ormagnetic permeability between the particle i and the surrounding fluid,f:2627 For example,when μi > μf, the effective magneticmoment of a particle has a positive sign, and the particle behavesparamagnetically; i.e., its dipole aligns parallel to the externalfield. By contrast, when μi < μf, pm becomes negative leadingthe particle to behave diamagnetically, i.e., with its dipole alignedantiparallel to the applied field. This latter case is the fundamentalconcept underlying “negative magnetophoresis”28 and the manipulation of nonmagnetic particlesin magnetic fluids. The analogous phenomenon of “negative dielectrophoresis”exists for electric field manipulation.29Despite the differencein their origin, electric and magnetic field-induced effects in colloidalassembly share a conceptual background; i.e., they can both be analyzedusing the point-dipolar approximation. Through this theoretical tool,a nano- or microparticle polarized by an external field is impartedwith a net dipole moment. This approximation is often useful to predictand interpret both electric and magnetic field-induced phenomena.A field-exposed particle may be approximated as an electric point-dipole, U:31E and H appearing, respectively,in pe and pm. Note that the above equations are applicableto colloids in a state where σ ≫ R.Point-dipole approximations are a commonly used tool to understandelectromagnetic interactions in colloids. These relatively straightforwardcalculations are particularly useful in predicting pseudoequilibriumstructures observed after exposing particles in suspension to externalelectric and magnetic fields.When the applied electric or magnetic field is uniform, themoment of a particle i communicates with the moment of a second particlej at a distance σ through a long-range potential that givesrise to the interaction energy Whileelectric and magnetic field-induced assemblies share an analogouspoint-dipolar approximation, the analytical treatment of active propulsiondiffers quite significantly between the electrically and magneticallypowered cases. Both fields generate propulsion by inducing asymmetricforces on the swimming objects because of asymmetry in shape and/orsurface. The difference is that the effects of the electric fieldextend to the suspending medium with most active motion deriving froman imbalanced electro-osmosis on the surface of an anisotropic particle.Conversely, magnetic fields only act on the magnetic domain of thesuspension, i.e., the ferromagnetic active particle and not the medium.In this case, the motion is achieved by nonreciprocal reorientationof the anisotropic particle by the magnetic torque which causes adrag imbalance on the surrounding fluid.34 is a successful analytical tool to describe activemotion in ac electric fields which will be discussed in further depthbelow. Briefly, the phenomenon indicates the motion of a metallodielectricparticle propelled because of asymmetric fluid flow caused by asymmetriccharging of the particle. At low field strengths and frequencies,the translational and rotational velocity, V andΩ, respectively, of the active particle propelled by ICEP isgiven by the following:34C and D are dimensionless tensorsthat share the symmetry of the particle and depend on its shape andcomposition. Due to the role of the electric field in polarizing thecounterion layer around the particle, ICEP is conceptually closerto fully locally driven active matter such as catalytic Janus particles.While powered by an external electric field, the role of the globaluniform field (time-averaged) is to induce a local field gradientin the vicinity of the geometric boundaries of the particle.Induced-charge electrophoresis(ICEP)35 or the collective motion of flocking ferromagnetic rollers.36That is not the case for magnetically actuated active motion, inwhich the external field magnetizes the particle which swims becauseof hydrodynamic coupling. Therefore, no equivalent of ICEP currentlyexists for the case of magnetic active propulsion. Instead, severalsuccessful models exist that analyze either the individual swimmingof a particle with a specific geometrysuprastructures, in an analogybetween the fields of supramolecular synthesis and supracolloidalassembly.37 The defining characteristicof assembly is its bottom-up nature, for which the final architectureis the net effect of the interactions among the building blocks andtheir packing. External electric and magnetic fields provide an additionalinteraction with a set of controllable parameters, namely, the strength,frequency, and orientation of the field, which act together with preexistinginteractions to drive assembly. Colloidal particles normally interactvia nonspecific interactions such as van der Waals attraction andelectrostatic repulsion and follow a thermodynamic pathway towardan equilibrium configuration.22 The exposureof polarizable particles to external fields implies the redrawingof their interaction energy landscape.38 This is how external forces direct assembly, effectively “pushing”particles away from equilibrium toward an alternative thermodynamicpathway, which is not accessible without the assistance of the field.Thus, in all assembly mechanisms that are driven by electric and magneticfields, the dissipation of external energy pays the cost of veeringoff the thermodynamic pathway. Research in field-induced assemblyis broadly classified into two categories equivalent to two typesof dissipative assembly.1 On one hand,there are assemblies of static suprastructures which maintain theirordered configuration once the external field is removed.40 On the other hand, there are assemblies of dynamic suprastructures,which only exist while external energy is supplied and will disassembleinto the constituent building blocks when the field is removed.3Colloidal assembly is the arrangement of micro- and nanoscale particlesinto structures of well-defined symmetry and configuration. The individualcomponents involved in the assembly process are building blocks connectingto form so-called 42 By tuning the relative alignment of the field and the particle suspensions,it is possible to control the directionality of the suprastructures.For example, one-dimensional assembly under electric and magneticfields is manifested in the formation of chainlike structures.45 These form as particles that acquire dipoles oriented in the samedirection, thus attracting each other in parallel with the field andrepelling each other when orthogonal to the field  chelates, whichsurpass the toxicity limit of cells. Parfenov et al. bypassed theissue by performing a bioassembly aboard the International Space Stationwhere gravity does not contribute to the force balance on cells electric field to arrange particles into two separate layers at thetwo electrodes. To this, they coupled an ac field used to controlthe magnitude of the dipolar interaction strength and found that theconfined layers respond to the change in energy landscape by forminga variety of complex phases such as zigzag stripes, honeycomb-Kagome,and sigma lattices as well as tetramer networks -coated substrates and atvery high electric field frequency.91 Thiswas termed self-dielectrophoresis (sDEP) indicating the occurrenceof a localized field gradient between the gold and the ITO surfacewhich leads to active motion of single particles. On a similar note,unbalanced electrohydrodynamic (EHD) flows on colloidal dimers showcaseactive propulsion with a frequency-controlled orientation.92Despite the intrinsic obstacles,nature found a way to achievedynamic motion at a low ectories 7b.11 The surface 7c.10 For93 Ina static homogeneous field, once aligned, a magnetized particle remainsimmobile. In a time-varying magnetic field, which originates froma rotating or oscillating ac electric field, the magnetic torque actsto continuously realign the particle.94 Thus, magnetic fields can induce active motion through anisotropyin particle shape and surface to overcome the scallop theorem. Liet al. fabricated flexible active nanoswimmers by joining togethernanowire segments of gold and nickel with nanoporous silver joints.95 The fishlike structure undergoes undulatorymotion when exposed to an oscillating magnetic field. The nickel sectionsof the nanoswimmer are placed in the center of the body, with thegold segments forming the head and the tail. This promotes the largestpossible deformation of the structure from the oscillating magneticfield, which causes a propulsive wave along the axis of the nanowires and hexadecane,sandwiched between two planar electrodes. Below a certain criticalfield strength, the particles rolled linearly while, above that fieldstrength, they display oscillatory dynamics  operating on a given colloid. A classificationof field-induced phenomena can also be achieved using dimensionlessratios of potential and kinetic energy associated, respectively, withassembly and propulsion. This allows the results from the literatureto be placed in a semiquantifiable spectrum based on the assemblyand propulsive forces underlying the phenomena, as shown in The traditional difference between assembly and propulsion becomesnarrower as more research reveals phenomena that interplay structureand dynamics. The application of an external electric and magneticfield inevitably affects both the morphology of assembly and the kineticsof colloidal motion. Depending on the characteristics of the field,of the particles, and of the medium used, the results can be moredramatically oriented toward an assembled structure or dynamics ofmotion. However, these two behaviors lie on a spectrum of nonequilibriumphenomena, and a precise definition of said spectrum is far from trivial.Statistical thermodynamics suggests that the proper quantificationof nonequilibrium requires a measurement of the entropy productionrate. Practically, this is extrapolated from the stochastic fluctuationsin a particle system which hide information on the amount of energydissipation.The toolset of electricand magnetic fields provides a large numberof design principles to control colloids out-of-equilibrium. Thesefundamental principles govern static and dynamic assembly as wellas passive and active motion. There are many exciting opportunitiesfor techniques on the verge of real-world applications, such as low-costanalytical techniques. In vitro tissue engineering using static magneticfields is still at the proof-of-concept stage, with the main challengesbeing the incorporation of magnetic nanoparticles often reducing cellviability and the difficulty in manipulating dense objects. Photoniccrystals made with electric fields may become a dye-free and thusmore sustainable way to achieve color in many applications.The strides made in hierarchical assembly have shown much promiseas a route to construct microarchitectures, whose functionality willundoubtedly be investigated in upcoming years. Some possibilitieswe envision are the incorporation of dynamic catalytic machines actuatedby magnetic fields within microreactors or the assembly of hybridmaterials comprising delicate microscopic parts or cells which wouldnot survive harsh lithographic processing.124 and environmental remediation.127 These include porous media, suspensions of macromolecules, and cellularenvironments. Further key research directions are distilled as follows:(1)understand the roleof thermodynamicsvs kinetics in the assemblies formed by weak, competing field-inducedinteractions(2)deconvolutethe respective roles ofparticle shape, surface chemistry, and dispersing medium in field-inducedcolloidal phenomena(3)find new methodologies to overridestochastic Brownian forces and achieve organized active motion atthe submicron scale by coupling multiple electromagnetic fields(4)develop new field-inducedcolloidalplatforms that respond to environmental cues and spontaneously self-regulatetheir structural and temporal characteristics(5)expand the domain of fundamental activematter research to advanced materials capable of performing sophisticatedfunctions such as energy transfer and mechanical work at the nanoscaleResearch of self-propellingcolloids is at a more fundamental stagecompared to assembly, yet synthetic motile microparticles have outstandingpotential in drug delivery, bioremediation, and also catalysis. Inparticular, we expect major advances in controlling motion withincomplex environments that are more realistic for applications suchas in biomedical devices129Assembly and propulsion are two of the mostfundamental phenomenain nonequilibrium colloid science. One must note that the attemptto bridge living and nonliving matter (as previewed in


In this study, an intelligent computing paradigm built on a nonlinear autoregressive exogenous (NARX) feedback neural network model with the strength of deep learning is presented for accurate state estimation of an underwater passive target. In underwater scenarios, real-time motion parameters of passive objects are usually extracted with nonlinear filtering techniques. In filtering algorithms, nonlinear passive measurements are associated with linear kinetics of the target, governing by state space methodology. To improve tracking accuracy, effective feature estimation and minimizing position error of dynamic passive objects, the strength of NARX based supervised learning is exploited. Dynamic artificial neural networks, which contain tapped delay lines, are suitable for predicting the future state of the underwater passive object. Neural networks-based intelligence computing is effectively applied for estimating the real-time actual state of a passive moving object, which follows a semi-curved path. Performance analysis of NARX based neural networks is evaluated for six different scenarios of standard deviation of white Gaussian measurement noise by following bearings only tracking phenomena. Root mean square error between estimated and real position of the passive target in rectangular coordinates is computed for evaluating the worth of the proposed NARX feedback neural network scheme. The Monte Carlo simulations are conducted and the results certify the capability of the intelligence computing over conventional nonlinear filtering algorithms such as spherical radial cubature Kalman filter and unscented Kalman filter for given state estimation model. The basic aim in state estimation of the underwater passive target is to accurately approximate the motion variables and target’s actual trajectory by obtaining valuable data from noisy measurements of hydrophones ,2. Real-In the literature, the famous Kalman filter (KF), following Bayesian methodology, is widely applied to solve state estimation problems for linear systems . In thisA serial Monte Carlo simulations-based technique, known as particle filter (PF), was introduced to handle the issue of non linearity by applying the bulk of particles for evaluating posterior density distribution . PF showIn the last decade, researchers have proposed many soft computing methodologies by following artificial intelligence studies. In these intelligence computing schemes, the strength of artificial neural networks (ANN) and optimization with local and global search algorithms are exploited . The speIn many practical engineering systems, whose characteristics are time-varying and which rely on their present state, non linearity is a big challenge to handle. In these systems, the NARX neural network paradigm can be convenient ,44. ReceIn our proposed study, we model NARX neural intelligence to approximate the current state of the underwater dynamic object in different ocean environments. Our key objective in this study is to design an appropriate framework to investigate the time series statistics of passive noisy measurements from the passive target. This proposed work establishes a novel state estimation application of neural networks to analyze different underwater scenarios for semi-curved trajectory of the target. The simulation results are compared with our recent reported study , in whicA performance based intelligent computing is presented for the accurate location estimation of a passive underwater target by manipulating the capability of NARX based neural network.Wiener Velocity Motion (WVM) model is exploited for designing the dynamics of target in semi-curved trajectory with the parameter of standard deviation of measurement noise.State estimates and position error for passive target prove the worth of proposed intelligent computing over conventional nonlinear variants of KF based on SRCKF and UKF.The performance is further endorsed through minimum RMSE criterion in terms of accuracy and better convergence rate than conventional nonlinear KFs.The numerical values of white Gaussian measurement noise are varied to assume cluttered and perfect underwater environment. Therefore, in the proposed study, NARX neural computing is investigated for position RMSE among actual and predicted location of an underwater kinetic vehicle. A comprehensive flow chart of the proposed work is illustrated in The rest of the study is organized as follows—In this portion of the study, a passive bearings-only state estimation system model is designed by following the state-space methodology. The kinetics of an underwater dynamic object are designed in a two-dimensional Cartesian coordinates system for precise real-time position estimation. There are eight acoustic sensors for collecting and combining passive bearings emitted from target. The passive bearings collected from acoustic sensors depend upon the horizontal angle and orientation of each array component. In the given system model, movement of the target is assumed in a continuous real semi-curved trajectory, which we aim to approximate with NARX neural network. This passive state estimation architecture is shown in In the dynamic model, target state vector consist on position e system . These mfined as:Sn=Fn−1SnMoreover, state-space methodology is also associated with the measurement model . At timeIn this section of the study, ANN modeling is briefly explained with a systematic description. ANNs, simply known as neural networks, are actually intelligent computing frameworks developed by the biological neural systems that integrate animal brains. A typical ANN is constructed from a set of bound nodes called artificial neurons. Each bound node is used to propagate signals between neurons. In our proposed study, NARX based ANN is designed for the accurate state prediction of an underwater target. Detailed modeling of NARX with its training method is explained in the below subsections.Here, the methodology of NARX neural intelligence is mathematically designed for state estimation of the underwater moving object. The importance of relationship among designed time series data and supplementary external data in real-life applications cannot be ignored. A common phenomenon in state estimation problems is that the performance of the estimation algorithm heavily depends upon noisy bearings. Therefore, the previous knowledge of noisy bearings can be handy for the modeling of time series to obtain better state estimation performance. A multilayer structure of NARX neural network is depicted in In the methodology of NARX, neural learning is applied for predicting future values in time series by efficiently incorporating previous data. External input and latter outputs of time series data are responsible for estimating the next value in nonlinear model of the NARX neural network. The multilayer structure of the NARX is designed with hidden layer, delay layer, input layer and output layer. Here we want to accurately predict state vector series l scheme , measurek error.y(n)=gv1 with steepest descent method (SDM). The working principle of LM training scheme is joint training procedure of neurons by initially quadratic estimation is conducted with SDM and after that weights are updated and improved with GNM. Minimum of function RMSE among true position and predicted position from state estimation techniques at each time instant Here in the simulation results and discussion section, the state estimates, position error, error histogram and regression analysis of proposed NARX neural scheme are comprehensively explained. Arithmetical values of measurement noise are accelerated from 0.1 to 2.5 radian for creating six different scenarios in the ocean environment. The least value of measurement noise LM algorithm is used to train NARX neural network in epoch form by following the Back-propagation algorithm through time phenomena. The network is trained using the in epoch wise mode. In the designing procedure, passive bearings collected at the acoustic sensors and true position data are used for estimation and evaluation of results. In overall time series, 70% data is used for training, validation is using 15% data and the remaining 15% data is used for testing purposes of the results. In this study, the LM algorithm is used to train the neural network. In the below figure MATLAB toolbox structure of NARX is given in which we give passive measurements State estimation framework consists of various parameters that need to be properly tuned for obtaining better performance from state prediction algorithms. The parameters and their relevent setting is selected on a similar manner as in reported studies ,19,21,22Here, MATLAB simulation results of SRCKF, UKF and ANN are conducted for estimating the real-time state of the passive moving target in rectangular coordinates. The performance of ANN for efficient state estimation is analyzed over six different scenarios of standard deviation of measured noise. These scenarios represent the ideal and noisy underwater environment in which the estimation capability of ANN is exploited. For each scenario, performance analysis of filtering and NARX neural network can be seen from Figure 6 to Figure 23 in the form of state estimates, position error, error histogram and regression of actual and estimated trajectory. Here six different variations of measurement noise are represented with their mathematical equations and simulations results as:In this scenario, standard deviation of measurement noise is taken as In In In In In scenario 1, an ideal underwater environment is taken by assuming the lowest value of the standard deviation of measured noise. The major observations in this scenario are explained as:In scenario 2, standard deviation of measurement noise is taken as In In In In The explanation of all simulation results is given as:In this scenario, the standard deviation of measurement noise is taken as In In In In Simulation results in this scenario are explained as:In this scenario, the standard deviation of measurement noise is taken as In In In In The major observations in this scenario are discussed as:In this scenario, standard deviation of measurement noise is taken as State estimates of SRCKF, UKF and ANN are presented in In In In Concluding remarks on simulation results of this scenario are given as:In the last scenario of this study, the standard deviation of measurement noise is taken as In In In In In scenario 6, a noisy underwater environment is taken by assuming the highest value of standard deviation of measured noise. Here simulation results are discussed as:Simulation results from all scenarios show that, for higher values of standard deviation of measured noise Along with the simulation results, we also compute RMSE in meters between the actual and predicted position of the target. These position error responses also endorse the above results that the accuracy of ANN is more than double from Kalman filters and it shows the effectiveness of neural network applications in the state estimation of passive target problems. These position errors computed from SRCKF, UKF and ANN are given in Intelligent computing through the NARX based neural network is investigated effectively for underwater bearings-only passive state estimation application. The instantaneous position of a passive dynamic target is predicted in two-dimension x-y coordinates at each time instant. Initially, bearings only and state space-based state estimation framework of dynamic and measurement model is mathematically designed. Later, the intelligent computing paradigm based on NARX is designed for the particular problem of the state estimation of the passive object. The NARX based supervised neural network is analyzed for 500 data samples. The competency of neural computing is assessed for semi-curved target movement in the form of minimum root mean square position error. Appropriate numerical values of the white Gaussian measured noise are applied to examine the performance of the proposed methodology. Simulation results clearly depict that the accuracy of the neural network is superior from conventional nonlinear filtering algorithms like SRCKF and UKF. In the noisy underwater scenario, the exponential decay is noticed in the results of all algorithms. Thus, obtaining accurate state estimation in a complex ocean environment is still a challenging task and has wide room for development.In the future, fractional evolutionary and swarming techniques ,51,52,53


Ascorbate is an important element of a variety of cellular processes including the control of reactive oxygen species levels. Since reactive oxygen species are implicated as a key factor in tumorigenesis and antitumor therapy, the injection of a large amount of ascorbate is considered beneficial in cancer therapy. Recent studies have shown that ascorbate can cross the plasma membrane through passive diffusion. In contrast to absorption by active transport, which is facilitated by transport proteins (SVCT1 and SVCT2). The passive diffusion of a weak acid across membranes depends on the electrostatic potential and the pH gradients. This has been used to construct a new theoretical model capable of providing steady-state ascorbate concentration in the intracellular space and evaluating the time needed to reach it. The main conclusion of the analysis is that the steady-state intracellular ascorbate concentration weakly depends on its serum concentration but requires days of exposure to saturate. Based on these findings, it can be hypothesized that extended oral ascorbate delivery is possibly more effective than a short intravenous infusion of high ascorbate quantities. Ascorbate is a compound indispensable for maintaining body homeostasis. It is necessary for a variety of metabolic processes ranging from the maintenance of the extracellular matrix to ensuring the effective flow of information between the cell genome and the proteome ,2. Its dIn the paper, the new model of ascorbate intake by cells, which accounts for the passive diffusion, is presented. The important consequence of ascorbate ability to penetrate the lipid bilayer is that the electrical potential of the plasma membrane and the local pH should be included in the evaluation of the steady-state intracellular ascorbate concentration . This opFor the sake of simplicity, the ascorbate-dependent single mechanism causing cell death was selected. Specifically, the sufficiently high concentration of ascorbate inside a cell may reduce ferric ions to highly toxic labile ferrous ions, which will likely lead to cell death by unspecific destruction of vital cellular components . TheThe model, contrary to previous approaches, is the first attempt to evaluate quantitatively the supportive treatment of cancer patients using ascorbate . The modAll calculations have been performed using dedicated Python (v3.8.10) scripts with NumPy v1.17.4 numerical library . Model’sIn the model, the human body with cancer has been reduced to two different populations of cells immersed in a single aqueous compartment. Selected parameters of cancer and healthy cells are listed in At the first approximation, the differences between the local tumor microenvironment and extracellular fluids in healthy tissues have been neglected ,30,31. TThe ascorbate treatment is simulated by the constant ascorbate concentration in the extracellular fluid compartment During the therapy, the Any therapy aimed at the eradicating of cancer cells relies on the differences between cancer and normal cells regarding their physiology and/or metabolic state, so the specificity of the therapy can be achieved. The ascorbate-based cancer treatment is based on the difference between healthy and cancer cells with respect to their sensitivity to extracellular ascorbate concentration. All previous ascorbate-based therapies were founded on the assumption that ascorbate affects a specific molecular process in cancer cells in a concentration-dependent meaner, in line with classical pharmacological thinking ,19. HoweThe intracellular concentration of ascorbate depends on the temporal cell metabolic activity and fluxes acres the plasma membrane (Equation (2)).+ concentration unchanged, the SVCT transporters will work with their maximum velocity (Vmax) [SVCT2) does not change. Therefore:It has been assumed that at elevated ascorbate extracellular concentrations (higher than 0.1 mM) and with extracellular Nay (Vmax) . Additiopassive) is represented by Equation (4) [nP and iP represent the permeabilities of the neutral and ionized forms of ascorbate. dfu, iC, rfu and eC represent the unbound fraction and total ascorbate concentrations in the extracellular (e) and intracellular (i) aqueous compartments. eH and iH represent the fraction of ionized ascorbate in the extracellular and intracellular aqueous compartments. eK and iK represent the respective neutral (protonated) fraction of ascorbate [The passive ascorbate transport depends, in addition to the membrane electric potential, on concentration gradients of its neutral and ionized forms, which in turn depend on local pH ,39. The tion (4) . In the scorbate .(4)JpasF,R and T stand for Faraday constant, membrane potential difference, gas constant and temperature, respectively.Equation (4) can be rearranged to the following form :(6)JpassFinally, the Equation (5) can be presented in the form:The net ascorbate depletion due to metabolic processes can be estimated as follows:The metabolic activity sumption ,40. The sumption ,42.It follows that the ascorbate intracellular concentration change can be formulated by the following equation:Since the therapy based on the ascorbate delivery is performed for an extended period of time, it has been assumed that the steady-state intracellular ascorbate concentration will be reached. Consequently, the intracellular ascorbate concentration can be calculated under the condition of the balance of all fluxes:Consequently,Since the ascorbate concentration in the serum and interstitial spaces is maintained, thanks to continuous supply, therefore the steady-state intracellular ascorbate concentration should satisfy the following equation:Equation (11) correlates the intracellular ascorbate concentration with its concentration in serum, which accounts for relevant cellular parameters. In order for the therapy to be effective, the intracellular ascorbate concentration should exceed the concentration required to release iron from its binding site triggering the ferroptosis . The difThe other important therapy parameter is its duration. For that reason, the time required to reach the desired steady-state intracellular concentration should be estimated. The dependence of the intracellular ascorbate concentration on time can be expressed in the following simplified form:The Equation (12) has a physically meaningful solution:Consequently,The time needed when the intracellular concentration reaches the value equals half of the steady-state intracellular ascorbate concentration, which can be calculated from the following equation: The main objective of the presented analysis is to design the effective ascorbate-based cancer treatment using the mathematical modelling.To describe the ascorbate-based therapy, two ranges of ascorbate concentrations in serum have been defined. The first range corresponds to the physiological level, which can be maintained by providing ascorbate with foodstuff (<0.1 mM) . InteresAll quantitative measures derived during the calculations describe a simplified situation, where two hypothetical cell populations representing healthy and cancer cells are considered . When hemax if the serum ascorbate concentration exceeds 0.1 mM and remains unchanged at higher values [The concentration of an exogenous active substance in serum is traditionally used as a therapeutic parameter, which is correlated with the flux of an exogenous active substance into cells. However, in the case of endogenous substances such as ascorbate, the descriptor is not very useful. The flow of ascorbate mono-ions towards the cytoplasm is facilitated by SVCT transporters and equals the Vr values . The intr values  and citar values ,9.First, the effect of extracellular ascorbate concentration and membrane electrical potential on the steady-state intracellular ascorbate concentration, both for healthly and cancer cells, has been evaluated . The calThe results presented in i) and extracellular pH (pHe) on the intracellular steady-state ascorbate concentration, when its extracellular concentration equals 0.2, 0.5 and 1 mM and plasma membrane electrical potential equals −100 and −10 mV for healthy and cancer cells, respectively. The numerical analysis shows that the intracellular steady-state ascorbate concentration is very sensitive to pH differences between extracellular and intracellular fluids. The dependence is further enhanced by plasma membrane electrical potential difference, confirming the cancer cell susceptibility to the elevated ascorbate concentrations. The three graphs in In healthy cells, the 20 mM intracellular concentration cannot be reached even when the treatment is continued for an extended period of time. Since the number of SVCT transporters in the plasma membrane is a parameter which can be controlled by adjustment of epigenetic processes by cells themselves and because its influence on the intracellular ascorbate concentration is significant , its effObtained results show the therapeutic effect can be achieved when ascorbate serum concentration is facilitated by supplementation using all available delivery routes as long as the exposure time is sufficiently long (days). The complete characterization of the procedure requires the evaluation of the therapeutic index as an indication of the procedure safety. Based on the proposed mechanism (ferroptosis) of ascorbate action, two toxicities can be expected; the induction of ferroptosis in healthy cells and systemic toxicity caused by dissociation of iron from transport proteins in serum. Both potential sources of toxicity await future quantitative evaluation.In classical pharmacology, the active compound is of exogenous origin and is designed to reach and affect specific molecular targets . TypicalAscorbate is a compound involved in numerous metabolic processes, so it may be considered a necessary element of intracellular homeostasis by serving as an electron donor or acceptor in various cellular compartments ,40. The Numerous experiments using cell culture show that ascorbate at concentrations above a few mM result in cancer cell death  intravenous infusion of its large quantities. The experimental validation of the model prediction will offer a very convenient and potentially effective supportive treatment of a variety of cancers.It has been demonstrated that pharmacological concentration of ascorbate in vivo cannot be reached by oral delivery of its classical form and that such delivery does not produce a sufficient level of hydrogen peroxide in extracellular fluid in vivo . HoweverThe effect of ascorbate on cancer cells in a solid tumor is not as straightforward as in the case of the isolated malignancy (presented model). The tumor environment will surely differ from extracellular fluid with respect to the importance for SVCT transporter sodium concentration, reduced local pH and hypoxia. They will change the dependence of intracellular ascorbate concentration on its local availability. The effect will not only change the steady-state conditions but also the dynamics of reaching therapeutic levels by the intracellular ascorbate concentration in cancerous cells.The concentration of ascorbate inside a cell is a result of three processes, metabolic degradation, active transport facilitated by dedicated transporters (SVCT1 and SVCT2) and the passive diffusion across the lipid bilayer of the plasma membrane. The dependence of the passive transport on ascorbate protonation and plasma membrane potential difference can be used for selective targeting of ascorbate to cancer cells. Specifically, most cells constituting the human body are highly differentiated. Such cells are characterized by, among other things, high negativity inside the plasma membrane electrical potential (reaching −100 mV). Cancer cells are different, as their electrical plasma membrane potential is usually low and does not exceed −10 mV. This difference can be used to elevate the ascorbate concentration in the cytoplasm of cancer cells without affecting healthy cells. This effect may justify the application of ascorbate as the supportive treatment in cancer therapy characterized by none or low systemic toxicity. Simulations presented in the paper show that such treatment to be effective requires maintenance sufficient, albeit not necessary excessively high, ascorbate concentration in plasma and interstitial fluids. However, due to the limited capacity of the active transport, the ascorbate exposure should be extended in time for days rather than hours.


Pinus radiata plantations. The economic losses in forest stands can be very severe because of its abundance in cones and seeds together with the low genetic diversity of the host. Pinus resinosa is not genetically diverse in North America either, and Diplodia shoot blight is a common disease. Disease control may require management designs to be adapted for each region. The genetic diversity of the pathogen could be an indicator of its virulence and spreading capacity. Our objective was to understand the diversity of Diplodia spp. in Spanish plantations and to compare it with the structure of American populations to collaborate in future management guidelines. Genotypic diversity was investigated using microsatellite markers. Eight loci (SS9–SS16) were polymorphic for the 322 isolates genotyped. The results indicate that Diplodia sapinea is the most frequent Diplodia species present in plantations of the north of Spain and has high genetic diversity. The higher genetic diversity recorded in Spain in comparison to previous studies could be influenced by the intensity of the sampling and the evidence about the remarkable influence of the sample type.Diplodia tip blight is the most ubiquitous and abundant disease in Spanish  Pinus radiata D. Don. is the most widespread exotic forest species susceptible to the fungal pathogen Diplodia sapinea (Fr.) Fuckel (syn. Diplodia pinea (Desm.) Kickx., Sphaeropsis sapinea (Fr.:Fr./Dyko and Sutton)) in Spain. The first record of the introduction of P. radiata D. Don in Spain is its presence in a garden in Lekeitio (Bizkaia) in the mid-19th century . Forest managers should be aware of forest ecosystem issues at global and local scales that will affect them directly or indirectly, such as the disease impact, epidemiology and genetic diversity of D. sapinea, which will lead to disease outbreaks when trees are physiologically stressed [D. sapinea) and new sources of entry of genetic diversity of the pathogen.Among the populations defined by sample type within the Basque Country, the cone population showed the highest genetic diversity based on the estimated parameters. These results are in accordance with the success and stability of hy trees . From thhy trees , this ststressed . DiseasePathogens impose strong selective pressures on their hosts. The way in which fungal populations respond to adverse conditions, such as those generated by control strategies, determines the risk of management failure due to pathogen adaptation conditioned by the type of genetic variability available.Changes in weather and climate may have implications for development of Diplodia tip blight. In northern Spain, spring temperatures have shown an increase over recent decades . Accordi


Trichuris spp. eggs from 6 different subjects. The algorithm evaluation was performed using a cross-validation strategy, obtaining a mean precision of 98.44% and a mean recall of 80.94%. The results also proved the potential of generalization capability of the method at identifying different types of helminth eggs. Additionally, the AI-assisted quantification of STH based on digitized samples has been compared to the one performed using conventional microscopy, showing a good agreement between measurements. In conclusion, this work has presented a comprehensive pipeline using smartphone-assisted microscopy. It is integrated with a telemedicine platform for automatic image analysis and quantification of STH infection using AI models.Soil-transmitted helminths (STH) are the most prevalent pathogens among the group of neglected tropical diseases (NTDs). The Kato-Katz technique is the diagnosis method recommended by the World Health Organization (WHO) although it often presents a decreased sensitivity in low transmission settings and it is labour intensive. Visual reading of Kato-Katz preparations requires the samples to be analyzed in a short period of time since its preparation. Digitizing the samples could provide a solution which allows to store the samples in a digital database and perform remote analysis. Artificial intelligence (AI) methods based on digitized samples can support diagnosis by performing an objective and automatic quantification of disease infection. In this work, we propose an end-to-end pipeline for microscopy image digitization and automatic analysis of digitized images of STH. Our solution includes (a) a digitization system based on a mobile app that digitizes microscope samples using a 3D printed microscope adapter, (b) a telemedicine platform for remote analysis and labelling, and (c) novel deep learning algorithms for automatic assessment and quantification of parasitological infections by STH. The deep learning algorithm has been trained and tested on 51 slides of stool samples containing 949  Ascaris lumbricoides and Trichuris trichiura, are common intestinal infections in low-income countries. Global estimates indicate that more than 1.5 billion people are infected with at least one STH species. They cause anaemia, gastro-intestinal problems, tiredness amongst other symptoms. Diagnosis of STH infection is mainly performed by analyzing stool samples under the microscope using the so-called Kato-Katz technique. However, the analysis of Kato-Katz samples, which is usually performed by microscopy experts, is a subjective procedure based on visual inspection of the samples and requires to be done in a short period of time since the sample preparation. In this work we proposed a novel system to digitize the microscopy samples using an affordable 3D-printed adapter and smartphones. Digitized images were uploaded to a telemedicine platform enabling remote diagnosis. Additionally, the digitized images were automatically analyzed by an Artificial Intelligence (AI) algorithm which was fully-integrated in the telemedicine platform, performing an automatic and objective count of different types of STH parasites (A. lumbricoides and T. trichiura).Soil-transmitted helminths (STH), including hookworm,  Ancylostoma duodenale and Necator americanus), roundworm (Ascaris lumbricoides), and whipworm (Trichuris trichiura) are the most prevalent pathogens among the group of neglected tropical diseases (NTDs) and occur predominantly in low- and middle-income tropical and subtropical countries  when compared to the results obtained with the conventional microscopy method, and a bias of -1.4 units, 95% confidence interval  when compared to the remote analysis of digitized samples.Additionally, we also executed the AI algorithm in all images extracted from all negative samples. The results showed that only 99 STH eggs were incorrectly detected  along the 20090 negative images, resulting in a specificity of greater than 99% at the image patch level.Trichuris spp. We extended our analysis by training the proposed method with all available subject samples, i.e. including those belonging to the one which were positive for a coinfection of Trichuris spp. and Ascaris spp. The training and evaluation of the extended version of the proposed method were based on a train-validation-test scheme. Of all available digitized slides from all subjects, 32 were randomly selected for training and validation, while the remaining 9 were used for testing. Both the training sets (70%) and the validation sets (15%) comprised 808 Trichuris spp. and 3649 Ascaris spp. eggs, while the test set (15%) consisted of 136 Trichuris spp. and 647 Ascaris spp. eggs. Our interpretation is that the appearance of helminth eggs is independent across slides and therefore the training and testing may be done using images from the same subject as long as they belong to different slides.For further assessment of the proposed approach, we also wanted to test the generalization capability of the proposed methodology at detecting other helminths eggs than Trichuris spp., Ascaris spp. and artifacts. Thus, background objects which are difficult to discern and are confused with real helminth eggs were used as negative examples.Additionally, and in order to increase the discriminating power of the proposed approach and to better distinguish between both helminth eggs and all those structures that may be present on the images which are similar to objects under study, we deployed our trained model on all training slides, identified all false positives objects, labeled them as a separated class (namely artifact class) and constructed a multiclass model including three different classes, namely Table 3 summarizes the results and proves that the proposed model can be extended for the detection of different helminth eggs, obtaining promising results, including a mean precision of 94.36% and a mean recall of 93.08%.Fig 4 shows the implementation of the AI algorithm on both technological platforms.The AI algorithm developed was integrated into both the telemedicine platform and the acquisition mobile app, allowing the operational deployment of the AI model so that it can be remotely used on demand by the telemedicine platform or even could be executed during acquisition time through the mobile app. Fig 4B). This could facilitate the identification and counting of STH eggs by the user.The execution of the AI algorithm on the telemedicine platform is done on a cloud computing platform. Each time the images are uploaded, the system recognizes the type of sample based on the image metadata and executes the AI model which will detect the eggs and show them in a visualization environment which is accessed via the web. As an additional possibility of integration of AI models into the clinical workflow, we have created a prototype that embeds the AI model in the acquisition app. While the user examines the sample with the smartphone attached to the microscope, the images captured by the camera are processed in real time, and all STH eggs detected by the AI algorithm locally executed on the smartphone’s hardware are shown in an augmented reality environment  and ensured enough ground truth quality to train AI models.Trichuris spp. eggs. The results validated the use of the proposed deep learning algorithms for the automatic identification of STH eggs. We also wanted to compare the results with those obtained with more complex and deeper network architectures, and the results proved that the proposed relatively simple architecture considerably reduces computational cost while maintaining similar results.Particularly, the proposed deep learning-based algorithm enables an automatic and objective identification of STH eggs. The method, which was trained and validated using a cross-validation scheme, achieved a relatively high precision and recall results  for the identification and classification of Additionally, the results obtained suggest that remote and AI-assisted analysis of digitized images of Kato-Katz samples allows to detect in mean more eggs compared to the count using the conventional procedure, since the analysis can be performed in a more exhaustive manner. Moreover, these tools would potentially be useful for other use cases such as the evaluation of the effectiveness of MDA programmes.Trichuris spp., we extended the analysis by training the algorithm including positive samples for both Trichuris spp. and Ascaris spp. coming from a co-infected subject. The results  showed that the proposed method can be extended for the detection of different STH eggs, although further validation work should be done in this direction.For further validation and to illustrate the generalization capability of the method at identifying other helminth eggs than It should be noted that the main limitation of this work may be caused by the relatively scarce number of considered subjects. This should be contemplated in future works in order to increase the variability regarding STH morphology and stage, appearance and aspect of the Kato-Katz samples and the inclusion of other species of STH (i.e. hookworm).Finally, we proposed an operational implementation which allows to integrate the AI algorithm on both the remote analysis platform and the digitization mobile app, opening a simple but potentially revolutionary use of the method on demand by invoking it through the telemedicine platform or in real time during image digitization with the mobile app.Next steps to scale the proposed system in the field require the undertaking of a large-scale clinical performance evaluation study to validate the entire pipeline and demonstrate its applicability where real-time diagnosis is required.Although effective and accurate molecular tools for the diagnosis of NTDs such as STH have been proposed, which are already implemented in developed countries , they ma