Cardio Vascular Diseases (CVD) is the leading cause of death globally and is increasing at an alarming rate, according to the American Heart Association’s Heart Attack and Stroke Statistics-2021. This increase has been further exacerbated because of the current coronavirus (COVID-19) pandemic, thereby increasing the pressure on existing healthcare resources. Smart and Connected Health (SCH) is a viable solution for the prevalent healthcare challenges. It can reshape the course of healthcare to be more strategic, preventive, and custom-designed, making it more effective with value-added services. This research endeavors to classify state-of-the-art SCH technologies via a thorough literature review and analysis to comprehensively define SCH features and identify the enabling technology-related challenges in SCH adoption. We also propose an architectural model that captures the technological aspect of the SCH solution, its environment, and its primary involved stakeholders. It serves as a reference model for SCH acceptance and implementation. We reflected the COVID-19 case study illustrating how some countries have tackled the pandemic differently in terms of leveraging the power of different SCH technologies, such as big data, cloud computing, Internet of Things, artificial intelligence, robotics, blockchain, and mobile applications. In combating the pandemic, SCH has been used efficiently at different stages such as disease diagnosis, virus detection, individual monitoring, tracking, controlling, and resource allocation. Furthermore, this review highlights the challenges to SCH acceptance, as well as the potential research directions for better patient-centric healthcare. I.Smart and connected health (SCH) refers to the solutions or systems for digital healthcare that are fully connected and can operate remotely Under the umbrella of smart cities, the use of digital technology, especially artificial intelligence, has been a focus of advancement, and healthcare delivery is no exception. Deloitte collectively identifies telecare, telehealth, telemedicine, m-Health, digital health, and e-Health services as connected health or technology-enabled care (TEC) The current COVID-19 global pandemic provides an excellent application scenario of the SCH: SCH adoption has proven its efficiency in pandemic management, tracking, and risk mitigation practices •The increased use of mobile technologies and smart devices has improved healthcare.•More innovative SCH for monitoring individuals’ health can further improve healthcare.•IoT integrates medical devices with the internet and provides/updates the real-time health status of patients to the consulting doctors.•Allowing different healthcare providers easy access to repositories such as the national health databank has enabled better monitoring of the COVID pandemic Unfortunately, cities have become hubs of rapid transmission in this pandemic. Rapid urbanization, population explosion, and global travel have worsened the situation. However, some countries were more resilient to the pandemic owing to the increased use of smart technologies such as the Internet of things (IoT), big data, AI, mobile technologies, and drones. In particular, China and Western democracies (the United States of America (USA), the United Kingdom (UK), Italy, Germany, Belgium, the Netherlands, France, and Spain), who were heavily affected in the initial three months of Covid-19 are known for adopting smart-city-based technologies Different governance mechanisms have been implemented by governments worldwide to control the pandemic, and surprisingly, their decisions were technology-driven and impractical at large. Although the extensive use of emerging technologies has improved the responsiveness to and control of the spread of the disease, this effect solely depends on the local governance and socioeconomic and cultural context This research work delivers a comprehensive state-of-the-art review on SCH systems, which assists the community of researchers and other stakeholders in the healthcare field to compare, comprehend, and build a clear understanding of the benefits of SCH systems. The proposed architecture is considered as a reference model to support healthcare stakeholders in realizing the technological perspectives, integrating the different SCH components, and building a complete SCH system. It emphasizes as well the main challenges which face the adoption of these systems in terms of usability, accessibility, data management and analytics, monitoring, and mobility handling. Additionally, it provides a future vision of the next-generation SCH solutions and systems.•Provide a classification model and literature review on various existing SCH models, solutions, and architectures.•Propose an architectural model that captures the SCH solution’s technical aspects, its environment, and the key stakeholders involved. Furthermore, the proposed model incorporates core innovations such as IoT, Big Data analytics, and AI to assist the primary stakeholders in improving the efficiency of the healthcare system.•Layout a case study on the adoption of SCH supported by evidenced data to combat the COVID-19 pandemic and illustrate how the pandemic was differently handled in terms of leveraging the power of various SCH technologies to identify, monitor/track and control the disease/virus; additionally, the present research focuses on the optimal technical resource allocation to combat the pandemic.•Identify key SCH challenges, and offer prospective research and technology paths for next-generation SCH, as well as provide recommendations for future SCH system implementations, taking into account the lessons learned from the present pandemic.This research aims to answer the following research question: how can we develop effective intelligent SCH systems and strategies to provide smart, efficient, proactive, patient-centric healthcare? To answer this question, we propose the following contributions.The rest of this paper is organized as follows: II.To classify and process the existing literature that reports the implementation, architecture, and solutions of SCH in healthcare, this study used the scoping research review approach.A.Papers were sought from scientific research databases and search engines  using specific keywords. Besides, we considered few relevant white papers. The following are examples of the keywords we employed: smart and connected health, AI in SCH, blockchain in SCH, IoT in SCH, robotics in health, applications of SCH, and SCH frameworks.B.The study selection procedures were followed after papers were selected based on the stated keywords. The papers collected have been screened and duplicates have been excluded with their digital object identifier (DOI). Initially, we divided the research papers into several groups according to the keywords used. This process was iteratively applied by all our research team members to ensure the validity of the conclusions. Consultations were made with clinicians and specialists in the medical field to further confirm the developed model. In three phases, the technique used for the review of the literature was carried out. C.We reviewed over 360 research papers and categorized the studies into five representative areas. Interesting observations concerning publishing patterns were found by the quantitative study of the article meta-data. Selected articles with respect to the year of publication and the count in the respective years are represented by a bubble chart in III.In this section we further review the literature and proposes a classification and a comparison of the existing work related to SCH, based on the enabling technologies, disease and pandemic monitoring (the application context), and futuristic systems.The classification shown in In the subsequent sections, we present and evaluate each of the above-mentioned clusters and summarize the work performed within each cluster.A.This cluster explores the healthcare impacts of AI and its various branches namely machine learning, deep learning, robotics, and virtual systems through a scoping literature review as seen in AI can be applied to structured and unstructured healthcare data. Common AI techniques include machine learning (ML), such as the classical support vector and neural network, and modern deep-learning based on neural networks. ML techniques typically analyze structured data such as data from images, genetics, and electrophysiological data. The ML methods used in medical applications attempt to cluster the characteristics of patients or infer the probability of disease outcomes Gaussian process regression (GPR) along with the relief feature selection algorithm was developed to achieve better performance than other ML algorithms in estimating systolic blood pressure and diastolic blood pressure BP Robotics is currently employed in various applications, primarily in challenging environments, ranging from material handling in labs to surgical procedures, and patient care Voice-activated assistants have numerous potential healthcare use cases, including those in the fields of education, health tracking, and monitoring; further, they can provide assistance in locating healthcare providers. The types of health and fitness applications available for voice-activated assistants fall in the categories of health education, fitness and training, nutrition, brain games, health surveillance, motivation, and meditation Virtual reality (VR) and augmented reality (AR) are novel technologies that can create an artificial world and allow the user to immerse in and interact with it; the use of these technologies can certainly raise the standards of healthcare and medicine Virtual humans The Virtual Brain B.This section explores the data and processing technologies and platforms supporting SCH, and the related studies are shown in The healthcare sector has become an emerging hub of big data users with the advancement of medical sensors in our daily life. For instance, the research kits from Fitbit and Apple can provide researchers with access to vast stores of user biometric data, which can then be used to test hypotheses such as those on nutrition, fitness, disease progression, and treatment appropriateness. Care providers may need to make critical decisions about the health of their patients using these huge volumes of health information provided in a multitude of data formats. State-of-the-art healthcare systems with IoT and big data analytics are proposed in The convergence of the IoT and the cloud introduced the so-called cloudIoT model, which aims to broaden both technologies and realize the next generation of smart healthcare apps. An innovative and sustainable healthcare system based on the game theory approach for cloudIoT st century Drones demonstrate tremendous potential for healthcare and medicinal transformation in the 21Trending mobile health  relationships with big data and insights can efficiently fulfill national healthcare demands in less-developed countries without fully open healthcare systems An emerging technology called mobile crowdsensing (MCS) has grown with the massive deployment of smart devices, and with the ubiquity of the Internet, appropriate data can be accessed for proper diagnosis and treatment in healthcare MCS (HMCS) C.The fourth industrial revolution in recent years has contributed to the so-called growth of the Internet of Robotic Things (IoRT) The majority of studies in the literature have emphasized the use of sensors to monitor patient health IoT-aware architecture for Smart Hospital Systems (SHS), which was proposed in Biometric data are the key to IoT operations, and biometric characteristics are used as signatures or as identity standards because they cannot be borrowed, purchased, or lost and are difficult to replicate or duplicate. Smart healthcare and IoT has ushered in a new paradigm in biometric data applications Security is one of the most critical issues of any type of information system. IoT technology constitutes an information network that enables data exchange between vast numbers of users and devices, and hence, security is a requirement. Two-factor authentication, with a smart-card and password, offering high security with the minimal computational cost is suggested in D.The studies referencing application context in SCH are classified into four main categories: disease management, monitoring, environment, and application awareness as depicted in SCH plays a major role in the field of medicine, from remote diagnosis to complex teleinterventions. It has also evolved to fulfill the growing demands for self-monitoring and disease management. Medtronic Health monitoring relies on rigid electronic housing coupled with aggressive adhesives and conductive gels, which cause discomfort and damage to the skin. In The applicability of SCH is suited to various environments, including, smart homes, health index monitoring Context computing is an ambient intelligence research branch that has rapidly evolved with intelligent smart health application solutions. Ambient context-based modeling was reported in Optimizing the energy consumption of IoT devices in continuous data-flow applications is a challenging problem highlighted in E.The future of SCH will definitely rely on smart hospitals and smart patient-physician interactions using smarter and innovative solutions. In the case of accidents, mobile apps will allow the network to geographically connect to the nearest hospital and transfer data before admission Predictive analytics plays an important role in the development of decision-support systems for the precise prediction and diagnosis of diseases. Its advantages in the healthcare sector far outweigh the potential challenges PillSense proposed in Using 5G and AI-based technology, we can drastically increase the level of patient care in rural areas and expand medical facilities in hospitals. 5G technology offers optimal alternatives, beyond wireless technology, to ICT-assisted health systems. A 5G-enabled ambulance can provide remote diagnosis and services, can automatically respond to an emergency call, and can choose an optimal route that can prove lifesaving. The high transmitting speed of 5G and its ultra-reliable low latency communication (URLLC) enables the remote operation of robots The autonomous ventilator proposed in IV.We discuss SCH solutions and the technologies that support them in this section, as well as propose an SCH architecture and detail an implementation scenario of CVD monitoring and how components and technologies included in the architecture can be used in practice.Data constitute the core of SCH wherein different technologies are used to gather, process, interpret and visualize data for more effective data-driven decision-making. The real challenge is not providing data but interpreting it to obtain valuable insights. Hospital reports contain historical data on patients and their medical records. Such data can be analyzed to detect correlations, patterns, and trends that can predict the probability of any disease occurrence in patients. Further, such an analysis can help select the best treatment options for the patients. For example, advances in automated image processing in radiology and pathology have revealed interesting insights that have improved the process of diagnosis. Machine learning is more effective in detecting lung cancer compared with detection by humans. Surgical data science is an evolving area in medicine and is witnessing fierce competition among medical equipment developers in terms of using approaches such as data mining to better compete in the market. Compared with humans, deep-learning algorithms can better detect trends when analyzing the patient’s historical data A.In this section, we propose an SCH architecture that we believe captures the technological aspect of the pandemic’s solution, the environment in which this solution can be applied, and the primary involved stakeholders. The proposed SCH architecture may be used according to the particular application for which it is used. Therefore, its adoption is subject to the context of the application, its purpose, and the main beneficiary of such solutions.As shown in 1)From the perspective of IoT, the SCH system resembles a single recognizable medical “thing” linked to the Internet (IoT). On a large scale, the SCH system may involve several “medical things” that can be interconnected through the Internet. For example, the management of patient data involves different settings for use in hospitals, homes, and ambulances; at times, this management is performed through smart remotely applied technology. Exploring new approaches to automating large-scale data collection in such varied scenarios is important. Crowdsourcing 2)The data ingestion layer represents the founding stage of the data-driven architecture presented here in 3)Application-specific processing, including local data collection, preprocessing, transmission, and retrieval over fog and cloud platforms are the essence of this layer. Mobile applications and drones that require real-time processing in tasks such as capturing violations of face-mask usage and implementing deep-learning techniques are some examples of such processing. AI seamlessly integrates virtual clouds and functional blockchain applications to assure secure health data transactions. Another example of smart processing is the use of a smart decision support model (SDSM) 4)Predictive analytics can be a central feature in healthcare delivery, and such platforms primarily rely on AI, deep learning, virtual reality (VR), and robotics. Analytics derives value from health data; thus, advanced analytical models are important for data-driven optimization and real-time decision-making in a health emergency 5)Real-time monitoring and alerting in case of seizures and drowsiness during driving, when blood sugar levels drop, or in fall detection among elderly people are different scenarios wherein smart technologies are prevalent. With more connected health devices, pandemic diagnosis, tracking, and visualization of data are critical for decision-makers. For example, smartness in visualization can be achieved by customizing the outputs according to the device screen size or resource availability 6)Successful SCH implementation will help healthcare planners in improving organizational and decision-making processes. SCH stakeholders, namely physicians, patients, healthcare providers, and active people, can have different roles and perspectives in the system depending on the adopted architecture.B.The leading cause of death worldwide is cardiovascular disease (CVD), and electrocardiography (ECG) is a commonly adopted method for quantifying cardiac activity to detect any heart defects V.Though COVID-19 is rapidly spreading, most people have experienced only mild to moderate symptoms A.Different countries are tackling the pandemic differently. In this case study, we focused on the countries that applied emerging technologies in conjunction with SCH for COVID-19 pandemic control and management. We found that using technology coupled with law enforcement helped in flattening the coronavirus curve and saved numerous lives in countries such as China, Korea, Vietnam, and Germany. This is in contrast to other countries, such as Italy and the USA, who have been unable to contain the spread of the COVID-19 pandemic.China reacted to the pandemic early on, whereas Italy was unprepared and underestimated the pandemic; similarly, the USA did not have a clear vision or a consistent strategy to control the pandemic. In this case study, we select three countries that reacted differently toward the pandemic. China adopted AI and big data technologies for tracking cases and modeling, efficient diagnoses, patient screening, vaccine development, and 5G enabled patient telemedicine. Alibaba Cloud Monitoring and surveillance technologies were well developed and effectively implemented. For example, smart sensor-based glasses were introduced by a Chinese company called Rokid China has emphasized the utilization of the existing telecom infrastructure to accommodate the required resources to face COVID-19. Therefore, there has been a 22.61% increase in the daily broadband network traffic, with the infrastructure supporting over a million 4G base stations, 75,000 5G base stations, and 170 million broadband subscribers, and providing a high bandwidth backbone to fulfill the requirements of the highest levels of data consumption With an increased demand for teleworking and distance learning, a myriad of multifaceted remote applications has emerged to support different industries, with over 700,000 users Unfortunately, authorities in countries such as the USA and Italy did not take the necessary measures needed to control the spread of the pandemic. Italy suffered numerous deaths that by the end of March 2020, constituted Italy’s highest number of casualties since World War II. Many reasons contributed to the loss of control over the spread of COVID-19 in Italy: the lack of data arising from unsystematic data collection in some hospitals and the lack of coordination between healthcare systems in public and private sectors, testing centers, and physicians China has been an exemplary model in terms of epidemic readiness and control. Its fast-paced tactics, innovation, and adoption of state-of-the-art technologies marked its success in the fight against the coronavirus B.AI, Big Data, IoT, Smart mobile applications, and Drones have been extensively used during the different phases of combating the pandemic including lockdown, movement tracking of the people, maintaining social distancing, and reducing healthcare workers’ proximity to patients. The following subsections provide different examples of technology-based applications as adopted by different countries in the fight against the pandemic.1)Smartphone apps provide tremendous opportunities to monitor the spread of COVID-19-related rumors, raise public awareness, enable mobile tracking, and enhance the delivery of preventive actions and clinical care TraceTogetherSingapore and South Korea combined different types of information such as location data, video, and credit card transaction information for tracking the virus. Singapore adopted the Aarogya SetuCOVID-19 FeedbackQuarantine Monitor Tamil NaduDifferent mobile apps were developed in India to respond to the pandemic. The government used phone call records, video surveillance, and cell location data for tracking the individuals who came into contact with coronavirus patients NCOVIBluezoneThe Ministry of Health in Vietnam adopted the Corona-Datenspende (Corona Data Donation) Germany promoted social distancing using information systems and technology, a strategy that yielded good results in controlling the virus. This is achieved through continuous testing and tracking of people. Different apps were developed for this purpose, such as, the Nevertheless, the government in the USA is still investigating the possibility of using the location information collected from Facebook, Google, and other vendors to track the virus; however, they are still facing several privacy issues nCappStop CoronaSocial Monitoring in Russia Civitas in Latin America StayHomeSafe in Hong Kong Coalition in the USA BeAware BahrainSome other mobile phone apps developed worldwide are as follows: 2)AI-based applications contribute to accelerating the diagnosis process of COVID-19, analytics, and predictions of the spread of the pandemic. For example, South Korea managed to contain coronavirus using AI-based diagnosis testing kits in less than a week. They developed a Chest X-Ray AI Image Support Decision Tool that identifies patients requiring immediate care within 3 s based on abnormalities in the lung X-ray images. Further, they launched an all-in-one medical platform named AiHub, which applies technologies based on AI and big data for the diagnosis of different diseases. The government also provided AI-based chat and voice robots that advise the public on ways to respond to the virus or call for help. The authorities are working on transforming affected cities such as Daegu into a smart city by 2021 to control a possible future wave of the pandemic Taiwan integrated its health insurance database with the immigration department using big data for analytics to assist in the diagnosis and generate real-time warnings based on travel information and medical symptoms 3)IoT-based drones can be used for different purposes, including surveillance, mass testing, announcement, diagnosis, delivery, and disinfection of areas 4)eXtremeDisinfection robot (XDBOT) equipped with wireless control and a mobile platform was used to disinfect contaminated areas, including the area under the patients’ beds Humanoid robots, autonomous vehicles, and other intelligent robots can help reduce physical interactions between healthcare workers and infected persons VI.There are several modules, processes, a multitude of technologies, variable application contexts, and diverse stakeholders involved in SCH systems that reveal a variety of challenges. In this section, we will address a couple of the relevant challenges in SCH, accompanied by future directions.A.Following are certain challenges that any potential SCH infrastructure must resolve in order to effectively function.1)IoT-enabled SCH poses major challenges to patient privacy. In SCH applications, a massive amount of data are continuously collected from and about patients. These data can be penetrated, copied, or deformed by unauthorized parties through malicious attacks such as tag cloning, spoofing, radio frequency (RF) jamming, and cloud polling. RFID tags that are not password-protected or protected by over-the-air (OTA) encryption can be cloned or replicated. An RF jammer is a device intended to prevent the reception of radio transmissions by a receiver relevant to its function. This type of attack can interrupt the functionalities of life-monitoring systems, sometimes causing loss of life. In cloud polling, traffic is redirected, allowing unauthorized command infusions directly into a device through a man-in-the-middle attack.In addition, denial of service (DoS) attacks can interrupt healthcare systems, consequently risking people’s lives. A common solution to DoS is redundancy; however, in a healthcare environment, resource duplication may not always be feasible. Many healthcare centers consider life-critical monitoring devices as extremely important to purchase and install. Hence, the prompt discovery of potential security threats remains a persisting challenge; with increased connectivity, the security threats are worsening. In SCH, wearable devices are used to accomplish critical health goals. However, the unavailability of security standards for these devices in conjunction with the ease of use of powerful search engines such as Shodan To integrate voice-activated assistants into healthcare, the design of voice-enabled user interfaces must consider the different needs of the end-users and their settings . However, the unique privacy and security issues that arise with the use of the devices that are always listening in the background To help tackle the spread of COVID-19, a wide range of surveillance technologies have been rapidly developed and deployed. This action has been justified by the argument that they are vital to suppressing the virus. In this case, civil liberties have been sacrificed for public health 2)A major challenge to SCH is connectivity. Many devices need to connect and continuously share data. Sensors of different types collect data and communicate with servers in their own language. Each manufacturer has their own communication protocol. Therefore, sensors manufactured by different manufacturers may not be able to communicate with each other. This divergence in communication protocols and software environments results in major challenges when designing large-scale SCH. Communication interfaces, data conversion and transformation, and protocol translation/conversion become a must, thus adding more technical complexities to the implementation of SCH.Furthermore, this enormously connected smart health system should allow patients and medical staff to move freely across several physical locations, which may be covered by different wireless networks, without interruption. However, mobility can result in collisions, particularly when several wireless networks operate within the near range. Collision causes many disruptions. It reduces the performance and may result in catastrophic situations, especially with regard to healthcare delivery. Consequently, ensuring that medical devices accurately operate when connected using different types of wireless technologies is crucial.Interoperability is a major requirement for efficient and successful SCH. A truly interoperable SCH system is one in which data can flow in one-to-one and one-to-many connections, generating the exchange of valuable data among multiple interfaces. This accentuates the need for devices that are compatible with various transmission formats and protocols.3)SCH systems utilize advanced technology that may not always be easy to use by physicians or patients. The presence of many features and configurations can, at times, make a system too complex, which subsequently discourages people from learning how to use it. Proper training and careful design of these devices are essential to ensure ease and continuity of use.4)The challenges of big data healthcare analytics are classified into data and process-related, manpower-related, domain-related, and organizational challenges 5)The introduction of IoT and mobile applications presents a range of challenges in terms of remote monitoring, connectivity capabilities, the nature of smart computing systems, and the provision of context-aware facilities. In IoT sensor networks, parameters such as the number of sensors are selected based on the application and user-specific needs The need for cooperation among multiple robots that share spaces with humans represents a key issue in smart robotic environments In predictive and personalized medicine, many AI-based deep learning models do not handle data of poor quality, and building a clinically useful prediction model is a challenge. At the personalized level, a predictive model should be continually modified, well-tuned, and delivered with ample time for early and successful clinician intervention. Owing to irregular or missing data and the variability of patient comorbidities and treatment, modeling the continuous existence of chronic diseases and development over time is a challenge B.This work evidently shows that the SCH system leverages new technologies to provide an efficient, cost-aware, fully connected, and powerful monitoring system. Considering the increasing network traffic, the following recommendations regarding capabilities of future traffic networks are inferred: incorporation of self-configuration, self-optimization, self-healing, and self-protection techniques Microblogging sites like Twitter and social media apps We expect that SCH will evolve and innovate to provide efficient, flexible, and cost-aware solutions, applications, and services to patients, healthcare practitioners, organizations, and even governments; this will enable the implementation of next-generation healthcare in the future. Its adoption by many countries will change the way of providing health services, monitoring patients, and managing diseases and pandemics.VII.SCH is an emerging research area that has attracted the interest of researchers, industries, and governments worldwide because of its potential to transform the healthcare sector into an efficient ecosystem. Herein, we explored this subject and proposed a comprehensive classification of the existing work on SCH solutions. This classification considered the main SCH-enabling technologies, the application contexts for which SCH is adopted, and the futuristic developments of SCH. We also proposed an architecture that pertains to the technological aspect of SCH solutions involving the environment in which SCH is deployed, along with the key stakeholders.The research also provided a bird’s eye view of the current COVID-19 pandemic in light of the developed SCH architecture and classifications. This will provide insights and guidelines to different stakeholders involved in the fight against the pandemic to develop more effective technologies and techniques. The processes and framework outlined herein describe details along with a case study on the strategies adopted by different countries in combating the pandemic. This further confirms the global reach of the problem and the need to join forces on a global scale to successfully control the pandemic using SCH. The work also attempted to address the present global crisis and endeavored to provide possible technological solutions and options. SCH clearly represents an effective solution in the fight against this catastrophic pandemic, which has thus far caused death and havoc everywhere, crippling the economies of several countries. Through the COVID-19 Pandemic Management case study supported with evidenced data, we proved that technology has helped in delimiting and decreasing the spread and facilitated in China’s comeback, which is not the case with other countries we have compared to like Italy and the USA. This research clarifies that the road to the full resolution of this pandemic is fraught with many challenges. One of the greatest concerns baffling health experts is related to the deaths of asymptomatic COVID-19 virus carriers. Data can shed more light on the causes of such deaths, for example, by revealing tacit patterns, and SCH, which is proficient in collecting and analyzing such data can play a decisive role in reducing and even preventing such deaths.It appears that COVID is here to stay for a while, and lockdowns and staying at home are not long-term solutions. However, living with the virus may likely be the new norm in human lives, and hence, the future seems to be a connected world with a smartly connected healthcare system. The pandemic has markedly accelerated the efforts toward building an SCH and has pushed many nations to re-prioritize their resources to infuse more ubiquitous smartness in their operations in general and in healthcare to combat COVID-19. SCH, with the advantages of improved quality of care and accessibility for all, will help transform reactive healthcare into proactive healthcare.The power of data obtained from multiple medical equipments, mobile devices, miniature sensors, and other sources can be harnessed by SCH. In addition, AI can provide insights, customize health experiences, and suggest lifestyle and wellbeing improvements to users at the cloud or edge, thus empowering them. To this end, our proposed architectural model of the SCH and the literature classification of the state of the art technologies and solutions provided insights to researchers and healthcare organizations to implement and deploy SCH to combat pandemic issues.Yet, there persist several challenges related to SCH adoption and the realization of the full potential of such solutions. The COVID-19 pandemic is one of the greatest medical and social challenges in decades. The pandemic has exposed the immediate need for a total transition to a modern healthcare paradigm. For emergency cases, SCH may no longer be considered an alternative or a complementary solution. It can be considered as a routine for patients with recurrent comorbidities for which treatment assures the appropriate quality of care. Now that the world is moving toward digital healthcare, emerging technologies such as IoT, AI, and telemedicine should be incorporated into international and national public health planning guidance. Improving the technical expertise of healthcare stakeholders, public training, and health data exchanges while fulfilling privacy and security requirements are the key challenges in SCH adoption.


Low tensile strength, poor elastic modulus, and complex concrete cracking work condition are almost unavoidable due to the intrinsic brittleness. To deal with concrete maintenance and durability, microbial self-healing concretes have been rapidly developed and widely applied recently. The microbial self-healing can specifically patch fractures as well as boost the concrete structure’s capacity, durability, and permeability. This paper presents the state-of-the-art in the microbe induced self-healing in cement-based composites. The microorganism and carriers were classified according to the working theory and repair effects. Additionally, the precise efficiency and effect of various technologies are also evaluated for microbial immobilization. Based on the literature review and summary from the perspective of microorganism, carriers, and immobilization methods, challenges and further works are discussed. Cement-based composites, including pastes, mortars, and concretes, are the most used construction materials in the world. However, it is also faced with surface cracks and deep internal micro cracks produced by gradient of temperature, plastic shrinkage, and settlement shrinkage. The cracks will absolutely impact a structure’s engineering performance and shorten service life, resulting in economic losses or even safety incidents . TherefoIn recent years, an innovative self-healing concrete based on microbial-induced carbonate precipitation (MICP) has become popular since calcium carbonate sedimentation was observed from Bacillus Pasteurella in the 1990s . A lot oThe basic illustration and working principle of microbial self-healing concrete is presented in The sustainable development of infrastructure requires the birth and development of concrete composite materials with self-healing capabilities. The significance of self-healing technology is to provide concrete infrastructure with the ability to adapt and respond to the environment, showing great potential and contributing to the creation of various sustainable materials and infrastructure. Due to an enormous amount of capital investment, continuous examination and safeguarding may be tricky to implement, particularly in the case of major construction projects; meanwhile, the development of microbial self-healing technology has become appealing due to the need for minimal labor and low capital expenditure.To understand the state-of-the-art of microbe-induced self-healing in cement-based composites, the development of microbial self-healing technology is reviewed in this article. The merits and defects of various forms of microbial and carrier materials are addressed, as well as the effects on the concrete remediation effect of the immobilization process. The aim of this paper is to promote the microbial self-healing technology as an alternative solution for ensuring the durability of concrete structures, as well as improve our understanding of the microbe induced self-healing in cement-based composites.3). According to the way calcium carbonate is produced, the general used bacteria could be primarily categorized into two sorts, i.e., urease bacteria and non-urease bacteria. Most of the urease bacteria and non-urease bacteria can resist the extreme environment inside the concrete and are thus suitable for carbonate precipitation in cement concreting.Microbial self-healing concrete is based on the bacterial-induced calcium carbonate precipitation . In natuVarious urease bacteria exist in nature, among which Bacillus pasteurii, Bacillus aerius, Bacillus sphaericus, Sporosarcina aquimarina, Bacillus megaterium, etc. are frequently proposed for the self-healing concrete. Bacillus pasteurii, a Gram-positive bacterium isolated from soil, can grow normally at temperatures ranging from 15 to 37 °C. The urease activities of Bacillus pasteurii is outstanding, which could rapidly decompose urea in the environment into ammonium and carbonate. Bacillus megaterium belongs to Gram-positive bacterium . B. spha3 precipitation and provide self-healing capacity in concretes. In metabolism, urease-catalyzing urea hydrolysis is secreted by urease organisms. As shown in Bacterial urease can hydrolyze urea, which will cause CaCOAccording to the research to induce the precipitation of calcium carbonate based on Bacillus cohnii, Bacillus pasteurii, and Bacillus sphaericus, in terms of the repaired width of cracks from microorganisms, the Bacillus cohnii self-healing performance in concrete specimens is more effective. The crack that Bacillus cohnii repaired had a width of 0.56 mm ; meanwhi3 and CO2 by using urease produced by themselves. In alkaline environment, the pH value of the solution with the increase of NH3 and CO2 exists in the form of CO32−.As for the non-urease bacteria, Bacillus pseudofirmus, Bacillus cohnii, Bacillus halodurans, Bacillus mucilaginous L3, Enterococcus faecalis, Geobacillus stearothermophilus, Bacillus subtilis, etc., are widely studied as non-urease bacteria inducing calcium carbonate precipitation. Bacillus subtilis is a Gram-positive bacterium that forms oval or cylindrical spores . NumerouFor non-urease bacteria, they will transform organic acids to form calcium carbonate precipitates through their own vital activities under oxygen-containing conditions. Calcium lactate or calcium acetate are often added to nutrients that non-urease bacteria can eventually convert to calcium carbonate. Equation (8) shows the reaction in which calcium lactate works as a carbon source .CaC6H10Most microorganisms are intolerant to alkaline environments. The Bacillus pseudoadamentosa has an exceptional ability to adapt to the alkaline conditions where the surviving pH value can be up to 11.0 . At 10 p3 crystals, whereas non-urease bacteria makes use of reactions by transforming organic acid into CaCO3 precipitation. However, the non-urease bacteria would not produce harmful gases such as NH3 and contributes an eco-friendly environment role in concrete.Overall, for the case of urease bacteria, it makes use of a series of reactions by itself to precipitate the CaCOMicroorganisms play an effective role in fixing concrete and preserving the mechanical properties and durability of concrete during the process of healing micro-crack concrete by microbial self-healing technology. Although a wide range of microorganisms can heal cracks greater than 300 μm under the right conditions, different types of microorganisms may have distinct healing effects. In microbial self-healing concrete, the healing results are influenced by significant factors such as whether to have carriers, how to use carriers, and how bacterial interacts with carriers.Inorganic porous carrier materials typically have porous surface properties and good absorption of water. The rich microporous structure will provide adequate room and sustain excellent connectivity for the growth and metabolism of microorganisms. Meanwhile, the comparatively thick surface can reduce the penetration of high alkali substances, which can significantly increase the tolerance of concrete bacteria.The lightweight porous aggregate carrier often belongs to the inorganic porous material; extended perlite, porous ceramist, diatomite, zeolite, pelelith, etc. are typical porous light aggregate carriers. These natural inorganic porous products are commonly used as a promising material in self-healing concrete for sustainable infrastructure, because they have strong compatibility with concrete and the characteristics of higher bacteria content, lower incorporated amount, and cost-effectiveness.The immobilization of bacteria inside expanded perlite (EP) shields bacteria from concrete’s high-pH climate and increases the self-healing to a large extent, enhancing the bending properties of concrete. Meanwhile, most of the bacterial treatments are restricted to the surface only up to few micrometers, and the use of expanded perlite can increase the healing rate in the deeper position of cracks. Numerous 100 mm cavities were found in expanded perlite particles using the Field Emission Scanning Electron Microscope (FESEM) and X-Ray Diffraction (XRD), which could provide free oxygen sufficient for bacteria inside the concrete and attachment space for the fixed bacteria to carry out their metabolic activities. At the same time, it can also make bacteria exposed to small amounts of water when cracks appear; thus, the expanded perlite exhibits excellent characteristics associated with high porosity and highwater absorption. The specimens incorporated with EP particles for B. Cohnii exhibit completely healed crack widths of up to 0.79 mm, which is larger than the value of 0.45 mm for specimens incorporated with expanded clay particles as  39]. A . A 39]. Diatomaceous earth (DE) particles are found to have a protective effect in a high-pH cement environment with porous properties; they have a strong capacity to sorb bacterial cells on the surfaces and provide a new microenvironment, which enables bacteria keep degrading urea . The finTo improve the loading content of the protective carriers, different pretreatment procedures, such as alkali erosion and sintering treatments, on lightweight porous aggregate were carried out beforehand. Ceramic particles as a carrier of bacteria were treated by NaOH solution with concentrations of 0.5 mol/L, 1.0 mol/L, and 1.5 mol/L to increase the number of loading bacteria . It is oBacillus pasteurella was found to survive in concrete (pH = 12) with the protection of zeolite and to produce calcium carbonate crystals after self-healing evaluation on crack-healed specimens at ages 4, 6, and 8 months cured in water, and the compressive strength improved with the addition of bacteria (10%) . HoweverPelelith can also function as a bacterial carrier to protect bacterial spores and investigate the repairing of concrete cracks. Compared to other carriers, the surface of pelelith is positively charged and its physical and chemical characterization are stable, making it more compatible with microorganisms and conducive to the settlement of calcium carbonate. Wu et al.  investigConsidering the factors such as local availability, cost, and protect impact of bacterial cells, advanced study focuses on bacteria that are immobilized via recycled coarse aggregate (RCA) and virgin fine aggregate (FA). It was found that using CA and 50% virgin FA as bacteria immobilizers exhibited the most effective crack repair method, which can heal a maximum crack width of 1.1 mm and restore 85% of the compressive strength while minimizing energy consumption and effectively lowering anthropogenic emission  is widely used as a waterproof material. The possibility of using silica gel or polyurethane as a carrier for bacterial protection was investigated by Wang . The actMicrocapsule is an artificial organic material, and this self-healing system has been developed mainly in polymers and composites, with the potential to provide bacteria with all around protection. Some microcapsule spores are used by researchers to isolate the outside world, which is helpful for resting and lurking spores . Spores Nanometer materials also contained artificial organic material which, due to the nanoscale size of the carrier, has certain advantages in improving the healing efficiency and performance of concrete. Khaliq et al.  have shoAs summarized in Although using the carrier would extend the life of microorganisms in an extremely alkaline environment, but the successful running time of existing bacteria is still inadequate relative to the real engineering application. Simultaneously, the inclusion of most carriers can affect the compressive strength of concrete samples to some degree, especially when multiple immobilized microorganisms die; thus, the resulting compressive strength of concrete will not fulfill the actual specifications for engineering. While microorganisms may be shielded from changes in the external environment and retain their biological action by the inorganic porous material carrier, the structure also creates considerable transfer resistance to the activities of bacterial existence. In addition, organic carrier materials have strong stability with microorganisms, but they are vulnerable to aging and decrease the repair effect. Therefore, the mechanical properties of carrier materials, their microorganism compatibility, and the resulting degree of concrete need to be further researched.The carrier mechanical properties can be changed by the qualitative alteration of surface groups or microporous composition of carrier materials, but it may come with a higher cost. Microcapsule technology is a great breakthrough in the future development direction of the carrier, it can effectively resist the mechanical force of concrete mixing, keep the microorganism active, and it has almost the highest healing rate among all the healing agents. The development direction of organic carrier materials in the future can be focused on the preparation of capsules, the mechanical properties of capsules, and the created empty space after healing. Meanwhile, the scale of the carrier can also be a great innovation. The incorporation of micro-scale carriers has a negative effect on the mechanical properties of concrete, while metal nanoparticles have a positive effect on the mechanical properties of concrete and its high compatibility with the concrete matrix. Therefore, the development of a nanoscale bio-concrete carrier is very promising and necessary. To facilitate the production and deployment of self-healing concrete technologies, we need pay more attention to find productive carrier materials and acceptable doses.A lot of microbial immobilization methods have been reported to immobilize the microorganisms into carriers to make microbes highly dense, to preserve microbes’ biological activity, and to proliferate microbes under ideal conditions . In micrCurrently, the vacuum impregnation method is one of the most commonly used technologies. The brushing method also has been used in microbiological self-healing concrete. The brushing method usually refers to the bacterial suspension and calcium source; nutrients are respectively brushed on the surface of the cement specimen, which can achieve the effect of repairing the specimen surface cracks. Among them, Qian and Ren  smeared ATM is often used with a shaker to mix the bacterial suspension with the carrier; then, it mixes the mixture with nutrients before adding it to the concrete. The adsorption experiment conducted by Wang et al.  showed tIn the process of microbial self-healing concrete, the immobilization procedure is also very important. The success rate and practicality of the microbial and carrier mixture would be influenced by the rational choice and implementation of the immobilization method. The combination of the microorganism and the carrier, which performs the protective role of the carrier, increases the survival rate of the microorganism, and eventually reaches the complete fix, will be supported by the proper method of immobilization. The selection of the immobilization approach only has some effect on the experimental results relative to the microbial species and carrier species that play a decisive role in the maximum repair width of concrete. Thus, when using same immobilization method, there may be a noticeable change in the maximum repair width of the concrete. Otherwise, if using the same type and quantity of microorganism, carrier, and nutrients, due to the different immobilization methods, in which the immobilization process, the immobilization effect, and the mechanism are different, there may be a various maximum repair width seeing , compresIn addition to the detailed description of microbial species, carrier types, and microbial immobilization methods that would impact the self-healing capacity, the working conditions especially temperature, water, the addition of nutrients, and even pressure are also important. The spores need to revive when the crack is producing. However, at different temperatures and different amounts of water, the spore recovery rate would be different, which will affect the calcium carbonate production rate. Furthermore, the amount and types of nutrients also should be considered; the addition of nutrients could promote the growth and mineralization efficiency of bacteria, as well as their ability to produce healing product. As result self-healing effect of concrete cracks could be improved. Moreover, in laboratory research, pre-cracking methods are also an important influencing factor. Many scholars use an electro-hydraulic servo testing machine, compressive servo testing machine, and automated bending compression testing machine to construct cracks. Each pre-cracking method will produce different crack widths and depths. When the crack is too large, the repair ability of microorganisms may not be enough to allow the crack to accumulate calcium carbonate, which makes the experiment unable to accurately evaluate the self-repair efficiency. Low pressure in a high-altitude area will affect the performance of cement mortar . It is nThere are two main categories to evaluate the self-healing capacity, which include the material detection method and physical inspection method. For the material detection method, scanning electron microscope (SEM), energy-dispersive spectroscopy (EDS), X-ray diffraction (XRD), and thermogravimetric analysis (TGA) are very common ways to investigate the morphology, energy distribution, and composition of crystals precipitated in cracks. SEM is a kind of observation method to obtain the microscopic morphology characterization of material by scanning with a high-energy electron beam. EDS uses X-ray photons to map the size distribution of energy. XRD is a technique for determining the crystal structure based on the diffraction patterns obtained from the emission of electromagnetic waves. TGA is a method of measuring the mass of a substance in relation to temperature or time. In addition, the physical inspection method concentrates on testing the self-healing capacity of concrete specimens, which includes compressive strength, flexural strength, water absorption, water permeability, durability, maximum repair width, maximum repair depth, etc. Meanwhile, the chloride penetration resistance can also be used to evaluate the self-healing capacity. Fahad et al. innovated the steady-state migration test under higher potential, and the self-healing capacity showed it can provide a more precise result .With the development of microbial self-healing technology, more and more microbial self-healing concretes have been applied in real projects. Since 2015, more than ten self-healing concrete demonstration projects have been reported in the Netherlands, the United Kingdom, Belgium, China, and other countries. It was applied to a variety of environments, including tunnels, water channels, foundations, etc. ,66,67.H. M Jonker developed a self-healing concrete with the spores of bacillus and natural fibers, and he successfully applied it as lining for an irrigation canal in the highlands in Ecuador. There are no signs of cracking on the surface of the lining after one year ,69. A reQian applied the produced microbial self-healing concrete to the side wall of the ship lock. It was observed that the cracking of the concrete was completely healed after 60 days, and the leakage of the crack was effectively blocked . These pThe current practical application of these microbial self-healing concretes provides a technical basis and reference for future large-scale usage as  showing,There is limited ability for a certain number of microorganisms to decompose the substrate and generate calcium carbonate. Sufficient bacteria need to be mixed to repair cracks. However, if too many microorganisms are present, the death of the inactive microorganisms would have some effects on concrete, including the mechanical properties, the permeability of water, etc. If very few microorganisms are mixed, the need for fixing cracks cannot be fulfilled. Therefore, the problem of the relationship between the specific number of microorganisms in the organization and the number of cracks must be solved.Nutrients are required components for microbial-mediated calcium carbonate precipitation in terms of microbial self-healing. However, the quantitative relationship between nutrients and microorganisms is still uncertain. The number of substrates would be abundant if microorganisms are insufficient, resulting in resource waste and an increase in cost. If the substrate is insufficient, the deposition of calcium carbonate will decrease, and the self-healing effect will deteriorate.There is a limited lifetime of microorganisms in concrete. Aeration is one of the most important factors influencing the survival rate. If a technology can be developed or a mechanism can be discovered to increase the lifetime of concrete microorganisms, it is possible to increase the self-healing effect and reduce the repair costs of concrete fractures later on.In concretes, there are mainly cracks on the exterior (not just on the surface) that have an effect on the whole. In this scenario, the procedure of surface brushing cannot fulfill the criteria for self-healing. However, in the concrete core, the carrier containing microorganisms and nutrients has only a limited repair impact, but the strength and permeability of concrete would have a great adverse effect. The self-healing impact of the central component of concrete, which can encourage advanced technologies and improve healing ability, can also be studied.It is unknown about the real survival rate of encapsulated bacteria after being introduced to concretes and the lifestyles of embedded bacteria within the concrete matrix. Up to date, although there are a lot of reports to explain the internal self-healing process of microorganisms in cement-based composites, researchers just presented certain inferences. The internal self-healing process of repair still needs to be clarified. The activity range, the mode of activity, the consumption process of edible nutrients, the path of repair, the speed of repair, and the cause of changes in the speed of repair for activated concrete microorganisms are still unclear. If the repair mechanism of microorganisms can be understood at the micro stage, it can clarify the reason that the surface of the cracks may heal entirely under the uniform distribution of microorganisms in concrete, whereas the deep cracks heal just half. Then, the experiment operation would be improved in order to achieve high performance and complete crack repair.The extent of a single microbial remediation is still unclear. If the scope of repair is precisely defined, the optimum self-healing effect can be accomplished by clarifying the optimal density of distribution of microorganisms on the basis that concrete performance is not affected by the carrier and nutrients. Or even if the carrier and nutrients have an effect on the concrete’s efficiency, the optimal self-healing effect can be calculated by a comprehensive consideration of the optimal density of microbial distribution. It is important to explain the relationship between the certain amounts of calcium carbonate produced by microorganisms and the producing time, and it is crucial to analyze the distribution type of calcium carbonate produced by microorganisms at the micro level. Whether calcium carbonate accumulates only in one direction or in all directions, which can determine the microbe quantity and achieve the best self-healing effect must be determined.The electro-hydraulic servo testing machine, compressive servo testing machine, automated bending compression testing machine, fishing line, iron nail, and other techniques are used by many academics in experimental research to generate cracks. However, in practical engineering, these man-made cracks are not the same as the cracks occur naturally. Therefore, it is important to make the same crack as the actual situation, which can increase the effective rate of crack repair in practical applications in engineering.The laboratory environment is the primary environment in which self-healing processes are studied. However, the concrete should be used in very different environments, such as marine water, rivers, soil, or frozen soil. In addition, it is necessary to consider some special situation, for example, the freeze–thaw cycles. Water can enter the concrete and dissolve the concrete matrix in each freezing period and thawing cycle due to changes in internal and external pressures. In this situation, the assessment of the effectiveness of a healing agent’s consolidation capacity is essential. Therefore, in order for practical engineering to have a great self-healing effect, these conditions should be simulated during research. The performance of microorganisms in various conditions should receive more consideration, and the final repair effect should be tested in the laboratory process.In addition to the performance of the self-healing process, the current production cost of the bacterial self-healing agent is also a challenge. To satisfy economic constraints, improved production methodologies will need to be developed, particularly with regard to the large-scale cultivation of bacteria, nutrients, and labor intensity. Strategies to increase bacterial self-healing efficiency and reduce costs need to be developed, which will accelerate the adoption of MICP-applied concrete in the future.In the field of microbial self-healing, due to the strong alkaline and poor living environment in concrete interiors, it is necessary to identify a microorganism with tenacious vitality, can resist strong alkalinity, and has an excellent repair effect. Otherwise, the interior of concrete is basically an anaerobic environment, so anaerobic bacteria will be more suitable for concrete self-healing. In addition, the mixed bacteria have more tenacious survival ability and can complete the task better, so we can use two or more microorganisms mixed in a certain proportion to make a mixed bacterium and try to study the repair effect. Genetic modification is also feasible, inserting exogenous DNA to achieve the necessary properties of the microorganisms needed for self-healing concrete. At the same time, the main reason for the lack of large-scale application of microbial self-healing concrete is its high production cost, especially the high cost of the cultivation of microorganisms and the use of nutrients. Therefore, it is necessary to find a lower cost of microbial culture methods and relatively cheap nutrients where the technology can have a better and wider application.The fundamental purpose of the carrier is to protect the survival of microorganisms under mechanical stress and high alkaline environment. In order to provide an excellent living environment and place for microorganisms, the carrier should have high porosity and great biocompatibility. The acquisition cost and application cost of the carrier should also be evaluated. In addition, the choice of carrier needs to consider the practical use of concrete. The performance of the level of concrete in different facilities and structures are different. Each structure has special features in some performance aspects and the effect carriers showed ultimately is different. Therefore, it is necessary to develop specific carriers for microbial self-healing materials with a series of special structures to exploit the structural strengths of each carrier. In the future, it will be important to improve the microbial immobilization methods or develop a new one that is easy to operate with higher efficiency.(1)3 crystals through a series of reactions, whereas non-urease bacteria convert organic acids into CaCO3 precipitates through their own hypoxic reactions. However, ammonia gas will be produced in this process when using urease bacteria, which is very undesire in artificial building materials. In the future direction of development, it is necessary to seek a more green and scientific way to fix ammonia, or through gene modification, insert exogenous DNA to achieve the necessary properties of microorganisms needed for self-healing concrete, such as alkalinity resistance, anaerobic, environmental protection, etc. The cultivation and nutrients of microorganisms account for a large part of the cost of microbial concrete materials. To realize the economical and practical use of this material, it is necessary to find a cheaper cultivation method and nutrients.The species and survival rate of microorganisms in microbial concrete materials need to be optimized. The microorganisms can be divided into urease bacteria and non-urease bacteria. Urease bacteria precipitate CaCO(2)The microbial carrier is an important factor that affects the self-healing efficiency of microbial concrete materials, which deserves more research. At present, carriers are mainly divided into organic carriers and inorganic carriers, which can work in different applications. Choosing a suitable carrier in the corresponding environment can improve the efficiency of self-healing to a certain extent. Despite the fact that the carrier can prolong the survival time of microorganisms in an extremely alkaline environment, the successful operation time of existing bacteria is still insufficient compared with actual engineering applications. It is necessary to develop more bio-affinity, high stability, and good compatibility carrier materials—for example, by changing the surface group or micropore composition of the carrier material, which can promote the production and application of self-healing concrete technology.(3)Microbial immobilization is an indispensable step in making microorganism self-healing concrete. Although there are many microbial immobilization methods at present, all of the methods and preparation conditions have corresponding standards, and each method has its own characteristics and merits. This paper focuses on the analysis of three commonly used methods which include ATM, MEM, and VIM and lists their repair effect. When the same microorganisms, carriers, and nutrients are used, and other variables are controlled the same, it will not have much impact on the final repair effect by changing the microbial immobilization method only. During microbial immobilization, special attention should be paid to the experimental operation process and method to avoid the decrease of the success rate of immobilization caused by unscientific and unprecise experiments, which will impact the final repair effect.(4)The microbial self-healing materials in the specific repair effect of microorganisms, survival ability, impact factor, and lifestyle in the concrete matrix are still unclear. The real application of self-healing concrete in civil engineering is still limited, and standardized methods for evaluate the healing capacity have not been established. The survival time of microorganisms in the concrete is limited. The current technology makes it difficult to know the actual survival rate of the bacteria after being introduced into the concrete. It is also difficult to determine the optimal distribution density of microorganisms. The research on the internal repair mechanism of concrete contributes to the development of more economical and practical microbial concrete.This paper focused on three main factors in the self-healing cement concretes including microorganisms, carriers, and microbial immobilization methods. The main conclusions are drawn as follows.


Cardiac amyloidosis (CA) is a rare systemic disease determined by the extracellular deposition of amyloid protein in the heart. The protein can accumulate in any part of the heart: myocardium, vessels, endocardium, valves, epicardium and parietal pericardium. The types of CA include the following types: light chain (AL), amyloidosis AA (Amyloid A) and transthyretin (ATTR). The detection of specific subtypes remains of great importance to implement the targeted treatment. We present the case of a 65-year-old woman, who was admitted with severe deterioration of exercise capacity, a bilateral reduction of physiological vesicular murmur, ascites and edema of lower extremities. CA was suspected due to echocardiographic examination results, which led to further examination and final diagnosis. The aim of this study is to improve the disease awareness among clinicians and shorten the delay between the first symptoms and the diagnosis establishment resulting in a better outcome. Amyloidosis is a disease entity in which proteins of abnormal structure gather in tissues . The bioIn July 2019, a 65-year-old woman was admitted to the Department of Internal Medicine due to severe deterioration of exercise capacity which has been gradually increasing since autumn 2018. There were also two episodes of syncope with body strains. In February 2019, the patient was hospitalized in the cardiology department, where a cardiac cause of the symptoms was excluded despite the increased serum level of NT-proBNP. In March 2019, she was hospitalized at the pulmonology ward, however despite comprehensive diagnostics, no diagnosis was made. At present admission physical examination showed a bilateral reduction of physiological vesicular murmur, ascites and edema of lower extremities. Laboratory tests showed an elevated serum level of NT-pro-BNP (5602 pg/mL) high sensitivity troponin T (81.57 ng/L) and creatinine. Electrophoresis of serum and urine proteins was performed in order to exclude diseases associated with hypergammaglobulinemia among others type AL amyloidosis and multiple myeloma. There was an increase in serum alpha 1 and 2 globulin with a simultaneous decrease in the gamma globulin fractions. Moreover, the albumin to globulin ratio and total protein concentration was normal. Urine electrophoresis did not detect immunoglobulin light chain. According to the results of electrophoresis, bone marrow biopsy was performed, which excluded multiple myeloma and other hematologic malignancies. The ultrasonography showed bilateral pleural effusion. MRI examination of pelvis confirmed massive edema of retroperitoneal and subcutaneous adipose tissue and inguinal lymphadenopathy. The echocardiographic examination  showed sThe patient had two episodes of syncope, after which an electrocardiography examination revealed sinus bradycardia (HR 35/min) and prolongation of PQ interval. During hospitalization, the patients was provided with furosemide and eplerenone, and a low-dose of bisoprolol which resulted in improvement of patient’s condition, and a gradual regression of edema and the amount of fluid in pleural cavities. Due to an unclear clinical picture and the suspicion of amyloidosis the patient was referred to the cardiology department for further diagnosis.At cardiology department cardiac magnetic resonance  revealedIn the presented case, despite the repeated hospitalizations, the diagnosis of ATTR was established with a long delay of 9 months. This might have been caused by various symptoms and the need to exclude other diseases. It confirms that amyloidosis is both rarely included in the differential diagnosis and the unclear clinical picture makes the diagnostic process time-consuming and complicated. Heart biopsy of an infiltrated myocardium is high risk procedure. Better availability of isotope scanning may limit severe complications of the invasive procedure ,8. HowevThe general CA treatment recommendations include the cardiac function support and the production as well as deposition of the precursor protein stopping  The loopThe TTR tetramer stabilizers include tafamidis and diflunisal. However, the first one is considered to be a better choice as its not associated with serious side effects , contrarThe TTR hepatic synthesis suppressors  both decrease the hepatic TTR synthesis and both are similar in effectiveness and tolerance .Amyloidosis is a rare condition, although it should be considered in patients with unknown reason for heart failure, especially in cases with preserved ejection fraction , as its


This study investigated the steady two-phase flow of a nanofluid in a permeable duct with thermal radiation, a magnetic field, and external forces. The basic continuity and momentum equations were considered along with the Buongiorno model to formulate the governing mathematical model of the problem. Furthermore, the intelligent computational strength of artificial neural networks (ANNs) was utilized to construct the approximate solution for the problem. The unsupervised objective functions of the governing equations in terms of mean square error were optimized by hybridizing the global search ability of an arithmetic optimization algorithm (AOA) with the local search capability of an interior point algorithm (IPA). The proposed ANN-AOA-IPA technique was implemented to study the effect of variations in the thermophoretic parameter  Nanofluids are defined as fluids that contain nanometer-sized particles (less than 100 nanometers (nm) in size), which are suspended in base fluids to enhance their convectional heat transfer. Nanofluidic problems of the flow and heat transfer characteristics are important from a theoretical as well as a practical point of view, and they have been extensively studied in applied sciences and various engineering applications, such as thermal power generation systems, the cooling of a large metallic plate in a bath, fiber spinning, glass blowing, melt spinning, wire coating dynamics and the extrusion of material through a die  were amoFe2O, alumina systems . Sheikho systems  analyzede shapes .In recent times, nanofluids have gained researchers’ attention due to their vast applications and their impact when combined with base fluids. In 2014, Rashidi  investigIn this study, a mathematical model of the steady two-phase flow of a nanofluid in a semipermeable duct in the presence of external forces was formulated by using the Buongiorno model and basic concepts of continuity and momentum equations. Further, the model was reduced to a system of ordinary differential equations.Moreover, to study the effect of variations in certain parameters, such as the thermophoretic parameter The results obtained with the proposed ANN-AOA-IPA technique were compared with the methods available in the latest literature. In addition, to study the convergence and stability of the results, the proposed algorithm was implemented for 100 independent runs.Extensive graphical, statistical and sensitivity analyses were conducted to study the errors in approximate solutions based on mean absolute deviations, Theil’s inequality coefficient and error in Nash–Sutcliffe efficiency.Generally, mathematical models of problems involving nanofluid flow are highly nonlinear in nature. Therefore, various methods in the literature have been developed to tackle such problems. The optimal homotopy analysis method (OHAM) has been used to study numerical solutions of the Cattaneo–Christov heat flux model ,16, nanoThe rest of the paper is organized as follows: In Consider the steady two-phase flow of a nanofluid in a semipermeable duct, as shown in  follows ,33:(1)∂vu and v are horizontal and vertical velocities, T is thermal quantity, and According to Raptis , the fluquations .(9)η=yaUsing Equation  will resThe corresponding boundary conditions for Equations –12) are are12) aThe Nusselt number In this section, we discuss the designed methodology for the solutions of the migration of nanoparticles in a duct with variable thermal radiation. The proposed technique consists of two phases. Initially, unsupervised ANN models in terms of mean square error (MSE) are constructed with the log-sigmoid activation function for Equations –12). In. In12). ANN-based models have been extensively used to study the approximate solutions of various problems arising in engineering and applied sciences ,33,35. TIn general, the nth-order derivative of the above models in terms of input, hidden and output layers is given asIn Equations –20), lo, lo20), Further, the suggested closed-form solutions and their derivatives are used to construct the fitness functions in terms of mean square error for the governing model of the problem along with the boundary conditions:minimizeΘThe arithmetic optimization algorithm (AOA) is a metaheuristic technique proposed by Abualigah  in 2021 X, which is given asThe arithmetic optimization algorithm begins the process of optimization by randomly generating a set of N candidate solutions MOA) function is used to determine the coefficient, which is defined asT represents the total number of iterations, tth iteration, and In the next step, AOA starts to improve the candidate solution by choosing the search mechanism , so the math optimizer accelerated  that are committed to the exploration search mechanism. Therefore, division or multiplication search strategies are used by AOA to explore the candidate space and find a better solution. This phase of searching is shown in r1 is a random number. Then, D will be executed if ith solution, jth position of the ith solution at current iteration, jth position, and MOP) is defined, in which the sensitive parameter This search is performed if In this phase, the search space is exploited in depth to find the optimum solutions around the candidate space. If Metaheuristic (MH) algorithms are high-level unsupervised learning techniques that are developed to solve complex optimization problems arising in various fields of physics, engineering, mathematics and medical sciences. MH algorithms are flexible, concise and vital in calculating solutions. However, in addition to these merits, they have some drawbacks. For instance, when dealing with complex optimization problems, AOA only utilizes the information of the best position in the population, which sometimes causes it to become trapped in a local optimum, which might affect the speed of the convergence of the algorithm. Therefore, the aim of this study was to develop a new hybridized algorithm to enhance the speed of the convergence of solutions in the local search phase. The solutions obtained by AOA are further tuned by a local search technique known as the interior point algorithm (IPA). It is used for the optimization of constrained and unconstrained optimization problems. Some recent applications of IPA include determining the solution of nonsymmetric exponential-cone optimization , convex The proposed ANN-AOA-IPA algorithm was implemented to study the effect of variations in various parameters, such as the thermophoretic parameter The approximate solutions obtained by the designed scheme are compared with the numerical solutions obtained by RK-4 and results obtained by machine learning algorithms, as shown in f, The suction parameter Furthermore, graphical analyses in To check the performance of the proposed algorithm in terms of stability, consistency and accuracy, ANN-AOA-IPA was implemented for 100 independent runs. Various performance indicators were defined to check the validity of the solutions. The formulation of these parameters  and error in Nash–Sutcliffe efficiency (ENSE)) are given asf, Here, The behavior of the objective/fitness function given in Equation  is shownA mathematical model of the steady two-phase magnetohydrodynamic flow of a nanofluid in a semipermeable duct was analyzed. Moreover, to study the system, a metaheuristic-driven approach was designed based on the intelligent computational strength of artificial neural networks. ANNs were used to model the structure of approximate solutions for the velocity, temperature and concentration profiles of the nanofluid. Furthermore, unsupervised models of solutions known as objective functions were optimized with the hybridization of global and local search techniques. The designed ANN-AOA-IPA algorithm was successfully implemented to study the influence of variations in the thermophoretic parameter


Here we present an extensive narrative review of the broadly understood modifications to the lifestyles of women with polycystic ovary syndrome (PCOS). The PubMed database was analyzed, combining PCOS entries with causes, diseases, diet supplementation, lifestyle, physical activity, and use of herbs. The metabolic pathways leading to disturbances in lipid, carbohydrate, and hormonal metabolism in targeted patients are described. The article refers to sleep disorders, changes in mental health parameters, and causes of oxidative stress and inflammation. These conditions consistently lead to the occurrence of severe diseases in patients suffering from diabetes, the fatty degeneration of internal organs, infertility, atherosclerosis, cardiovascular diseases, dysbiosis, and cancer. The modification of lifestyles, diet patterns and proper selection of nutrients, pharmacological and natural supplementation in the form of herbs, and physical activity have been proposed. The progress and consequences of PCOS are largely modifiable and depend on the patient’s approach, although we have to take into account also the genetic determinants. Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy, affecting as many as 15% to 18% of women of reproductive age . It seemMany studies have shown that higher hormone levels, gut microbiome composition, and plasma metabolomics are new parameters related to the PCOS phenotypes . The clidisorders of gonadotropin hormonal synthesis;the appearance of insulin resistance;the influence of the present excessive body fat; and finally,the metabolic pathways involved in PCOS   7]..7].The four main causes of the physiological basis of PCOS include:Appropriate functioning of the mechanisms responsible for the maturation of the ovarian follicle and its ovulation depends on the proper physiological activity of three organs: the hypothalamus, pituitary gland, and ovaries.The mechanisms of hormonal regulation in the hypothalamic-pituitary-ovarian system take place through the axes of negative feedback: long, short and ultra short feedback. In the suprachiasmatic nucleus of the hypothalamus there are neurons synthesizing gonadotropin-releasing hormone (GnRH), which is released into the pituitary portal circulation in the median eminence. GnRH release is regulated by a network of interconnected neurons. Gonadoliberin is an example of a hormone secreted in a pulsatile rhythm, and the frequency of this rhythm determines the type of gonadotropin released. A low frequency of gonadoliberin pulses results in the secretion of follicle-stimulating hormone (FSH), while a high frequency results in the secretion of luteinizing hormone (LH) from the anterior lobe of the pituitary gland. LH is responsible for the luteinization of the corpus luteum, i.e., the transformation of granulosa cells into theca lutein cells which produce progesterone. In turn, FSH stimulates ovarian follicle maturation and estrogen secretion in the granulosa cells of ovarian follicles. It also increases the activity of aromatase, the enzyme responsible for converting androgens (testosteron and androstendion) to estrogens. When the concentration of luteinizing hormone increases relative to FSH, excessive androgen production occurs, which is more common in women with PCOS .Insulin, both directly and indirectly, affects the pathogenesis of PCOS. It acts synergistically with luteinizing hormone, increasing the production of androgens (theca cells) and decreasing the liver synthesis of the main binding testosterone protein (SHBG), which results in testosterone circulating in the unbound, active form . Excess The activity of leptin affects the function of the hypothalamus–pituitary gland–ovary axis by modifying the secretion of GnRH, LH, and FSH. Leptin is a signal for the hypothalamus to release LH, causing the secretion of pituitary GnRH, as well. This can result in excessive androgen synthesis. Adipose tissue, by secreting pro-inflammatory factors such as mentioned cytokines, contributes to the development of inflammation in PCOS and an increased amount of free radicals caused by hyperglycemia; excess adipose tissue and androgens contribute to the formation of chronic inflammation in PCOS .The various clinical symptoms of the disease indicate that many metabolic pathways participate in PCOS development, including: secretion and activity of insulin, with genes encoding for insulin receptor (IR), insulin (INS), and insulin-like growth factor (IGF) and its receptor; genes encoding for steroidogenesis; genes responsible for the activity of cytochrome P450 ; and other metabolic and hormonal pathways, with genes for androgenic receptor (AR), LH receptor, leptin, and follistatin . ModeratWeight gain mediates most of its direct medical sequelae through worsening insulin sensitivity.Insulin resistance (IR) plays a key role in the development of metabolic dysfunction, including hypertension, dysglycemia, and dyslipidemia. A large amount of evidence supports a role of mitochondrial dysfunction in the development of IR, stimulated through ectopic fat deposition. Lipid-induced production of reactive oxygen species (ROS) within skeletal muscle promotes mitochondrial dysfunction and the development of IR . UltimatThe cellular effects of insulin occur through two main post-receptor pathways: the phosphatidylinositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways . The PI3The association between body weight and IR is mediated through inflammatory pathways . ObesityIncreases in ROS generation, p47phox gene expression, and circulating thiobarbituric acid-reactive substances (TBARS) occur in PCOS in response to saturated fat ingestion independent of obesity. A diet rich in simple sugars, as well as saturated fatty acids additionally enhances the production of ROS by different mechanisms, including the influence on gut microbiota . Circulaα secretion from circulating leukocytes [Superoxide is a ROS produced when NADPH is oxidized by membrane-bound NADPH oxidase . Dysreguukocytes ,25. In oukocytes . Women wukocytes .Many studies have targeted the inactivation of the transcription factor (NRF2) as a therapeutic approach in various types of cancer . NRF2 waIt has been found that there are at least three pathways controlling the stability of NRF2. The first one depends on the cytosolic repressor KEAP1 ; the secThe abnormal activation of the NRF2/KEAP1 pathway promotes cancer development , metastaBifidobacteria correlates with insulin secretion and increased glucose tolerance, regulates IR, and helps reduce inflammation. Short-chain fatty acids (SCFAs) such as acetate and butirate produced by the beneficial gut flora influence glycemia through glucagon-like peptide 1 (GLP-1) and pancreatic polypeptide (PPY), which are intestinal hormones [The structural and functional dysbiosis of the gut microbiota in high-fat diet (HFD)-induced obesity was demonstrated in a mouse model . The michormones . The horhormones . Due to hormones  in combahormones , as wellhormones .Lifestyle change is the first line of treatment for the management of women with PCOS but is not an alternative to its pharmacological treatment . RegularNutritional counseling for PCOS patients has been one of the treatment methods for many years. However, strict caloric restrictions do not produce the expected long-term effects ,54, and α and peripheral leukocytic suppressor of cytokine-3 (SOCS-3) expression [Analysis of the impact of lifestyle modification related to the share of energy from macronutrients  showed no significant differences in the levels of the analyzed parameters. However, a significant factor in these changes was the reduction in the caloric content of the diet  and the pression . Therefopression .The effects of soluble dietary fiber on SCFAs were demonstrated. Fermentable fiber has positive metabolic benefits on the gut microbiome with subsequent release of SCFAs . Diets wIt seems that another reduced-GI diet modification is the ketogenic diet, which limits the consumption of total carbohydrates in favor of plant-based fat. The ketogenic diet (KD) improves the menstrual cycle, reducing blood glucose and body weight, improving liver function, and treating fatty liver in women with PCOS and liver dysfunction who were obese . Even moExercise training in the management of PCOS is becoming more recognized and accepted among professionals in the health sector and the patients. Physical training potentiates the effects caused by insulin sensitivity through the optimization of glucose transport and metabolism .p = 0.01; MD-1.90, 95% CI −3.37, −0.42, and p = 0.01), respectively [A recent meta-analysis found that improvements in health outcomes are more dependent on exercise intensity than dose. The results from this analysis support the use of exercise and that vigorous intensity exercise may have the greatest impact on cardiorespiratory fitness, insulin resistance, and body composition . Insulinectively . Other aectively . The minectively .Mental health disorders are highly prevalent in PCOS cases, which are associated with significantly more frequently experienced states of anxiety and depression, as well as sleep disorders . Sleep dBased on current knowledge, it is plausible to conclude that sleep disorders can be considered as one of the first symptoms leading to the weakening of the body’s protective properties and intensification of the pathways associated with insulin resistance in the course of PCOS.The research showed that the vast majority of women with PCOS consume an improperly balanced diet, involving deficiencies in fiber, omega 3, calcium, magnesium, zinc, and vitamins  . An exceWhile drawing attention to the potential properties of blood vessel protection in PCOS, supplementation with coenzyme Q10 also requires consideration. CoQ10 supplementation for 8 weeks had a beneficial effect on inflammatory and endothelial dysfunction markers in overweight and obese patients with PCOS .When analyzing the available literature on supplementation in PCOS, attention should be paid to vitamin D, which increases insulin synthesis and release, increases insulin receptor expression, and increases insulin response to glucose transport . VitaminCurrent results showed that myo-inositol is as effective as metformin in improving the clinical and metabolic profile of women with PCOS and the metabolic disorders associated with diabetes . HoweverAs in traditional medicine, natural substances such as isoquinoline alkaloids have been used to regulate the synthesis of androgens and the metabolism of lipids and carbohydrates, the introduction of berberine in patients with PCOS has been considered ,98,99. AChromium is the basic element involved in the metabolism of carbohydrates and lipids; therefore, it has become one of the most commonly consumed dietary supplements in the USA . The indThe research, and the available literature, show that supplementation with zinc and selenium to counter deficiencies may be indicated in the case of at least some patients with PCOS. Due to intracellular signaling and structural functions, zinc plays a role in lipid and glucose metabolism and fertility . Low zinAloe vera, cinnamon (Cinnamomum verum), green tea (Camellia sinensi), and chamomile (Matricaria chamomilla), and white mulberry  [Maiorana hortensis) are some of the herbs whose effects include improvements in hormonal levels, ovaries weight, insulin sensitivity, antioxidants, and anti-inflammatory parameters [A balanced diet to support insulin management is the most important treatment for PCOS; drinking infusions of some herbs would therefore be a very good complement to the therapy, such as us alba) . There aus alba) . Becauseus alba)  and marjrameters ,118.Mentha spicata L.), which has an antiandrogenic effect and restores follicular development in ovarian tissue [Glycyrrhiza glabra) has been used in the treatment of PCOS because of its antiandrogen and estrogen-like activity. Licorice root appears to be effective in reducing excess testosterone as it blocks the conversion of androstenedione. Glycyrrhetinic acid and metabolites block 11 beta-hydroxysteroid dehydrogenase type 2 and bind mineralocorticoid receptors directly, acting as agonists [Serenoa repens, Camellia sinensis, Rosmarinus officinalis, and Glycyrrhiza glabra can also lower androgen levels and inhibit androgenetic alopecia [Vitex agnus-castus is a good regulator of the menstrual cycle and has been used in traditional medicine for centuries [Linum usitatissimum) may alter the activity of key enzymes involved in estrogen synthesis  to modulate relative levels of circulating sex hormones and their metabolites [Another group of herbs is indicated especially for women with PCOS with biochemical evidence of increased levels of androgens: green mint , and specifically curcumin, is a biologically active phytochemical ingredient [Urtica dioica) is a multipurpose herb in medicine for which some antioxidative, anti-inflammatory, antimutation, and antitumor properties were identified [Turmeric  [Cynara Cardunculus) extract [Taraxacum officinale) and its component taraxasterol may silence the gene of SIRT1, preventing the disruption of hepatic cells [Nigella sativa) also has similar properties, which should be included in the diet of obese PCOS patients [Ultimately, in advanced PCOS with accompanying disease associated with metabolic syndrome and the steatosis of internal organs , herbs and their extracts with proven properties should be considered for their hepatoprotective activities . These sarianum) ,138 and  extract ,140. Danic cells . Black cpatients . To summCurcuma longa), improving liver steatosis  and the frequently occurring intestinal dysbiosis (probiotic therapy). Conducting our own research in this area, we examined how increasing the supply of vitamins and minerals with the diet affects the supply of these components in patients, so we also searched the literature and described suggested supplementation . Undoubtedly there is a need for further research to be undertaken to determine the efficacy and applicability of the ingredients described as a support for traditional PCOS management.The analysis of metabolic symptoms occurring in the course of PCOS points to the need for a multidirectional therapeutic approach. The metabolic pathways leading to the abnormalities are presented, which requires focusing on the improvement of parameters related to fertility, hirsutism, the occurrence of carbohydrate-lipid disturbances and the reduction of insulin resistance. One of the most important pathways for blocking carcinogenesis is presented. It has been shown that significant improvement of these parameters depends on modifiable factors related to the improvement of lifestyle, the introduction of a diet, especially a low-calorie diet with reduced GI, normalization of sleep and the introduction of daily physical activity. In addition, supplementing the diet with antioxidants and herbs seems to be highly effective in combating the chronic inflammation  databases from the last 20 years.All articles collected through the electronic search process used in this article were reviewed from the abstract. Articles unrelated to the main topic, duplicate papers in both databases (PubMed and Embase), and conference abstracts were excluded from the review process. Only articles published in English were considered.The main core of the issue was the authors’ own 10 years of experience and research in this patient group. From the authors’ own studies, those that corresponded sequentially to the intervention steps discussed were selected. The physiological basis was discussed (searching the database for PCOS and insulin resistance or chronic inflammation or endocrine disorders or cancer or microbiota). Lifestyle changes were then discussed. Studies that examined the association between PCOS and diet or supplementation  or adjunctive herbs were included in the review. In the case of duplication of information in publications, those that contribute most to the main topic were selected.