The 5G wireless communication network is currently faced with the challenge of limited data speed exacerbated by the proliferation of billions of data-intensive applications. To address this problem, researchers are developing cutting-edge technologies for the envisioned 6G wireless communication standards to satisfy the escalating wireless services demands. Though some of the candidate technologies in the 5G standards will apply to 6G wireless networks, key disruptive technologies that will guarantee the desired quality of physical experience to achieve ubiquitous wireless connectivity are expected in 6G. This article first provides a foundational background on the evolution of different wireless communication standards to have a proper insight into the vision and requirements of 6G. Second, we provide a panoramic view of the enabling technologies proposed to facilitate 6G and introduce emerging 6G applications such as multi-sensory–extended reality, digital replica, and more. Next, the technology-driven challenges, social, psychological, health and commercialization issues posed to actualizing 6G, and the probable solutions to tackle these challenges are discussed extensively. Additionally, we present new use cases of the 6G technology in agriculture, education, media and entertainment, logistics and transportation, and tourism. Furthermore, we discuss the multi-faceted communication capabilities of 6G that will contribute significantly to global sustainability and how 6G will bring about a dramatic change in the business arena. Finally, we highlight the research trends, open research issues, and key take-away lessons for future research exploration in 6G wireless communication. The commercialization of 5G commenced in 2019, and further adoption is expected in 2021 and beyond. There have been tangential research interest on future 6G wireless networks , connect7 connections per km2 [6G is expected to have data-rates in the order of terabits per second and a latency of less than 1ms. It is expected to drive the Internet of Everything, with 10 per km2 ,12, whic per km2 . Explori per km2  such as  per km2  and Free per km2  are discAdditionally, technologies such as Reconfigurable Intelligent Surfaces (RIS) ,18,19, cDespite the auspicious view of this technology, challenges with complex data and more have been highlighted. These challenges have been delineated in this article. Other enabling technologies such as Quantum Communication , AmbientEnergy efficiency is another interesting topic for future wireless networks. It is desirable to have hardware that is compatible with the energy requirements of 6G. Ambient Backscatter Communication Systems (ABCS), an Energy Harvesting (EH) technique, is proposed to enable wireless charging. This gives room for longer battery life, which has been proposed as a requirement for future wireless networks . With thSeamless and fast ubiquitous communication is also desirable in 6G. UAVs and CubeSats, which form the Internet of Space things , will faThis paper provides researchers with a guide to what 6G will be. It proposes a panoramic vision of 6G, the enabling technologies, and the associated challenges. This makes the paper to be robust, compensating for the individual lapses in the existing literature. Additionally, we provide an extensive analysis of the social, psychological, health, and commercialization challenges associated with 6G, which are missing in earlier reports to the authors’ best knowledge. The article also introduces new use cases of 6G in education, media and entertainment, tourism and transport, and logistics, which have not been given adequate treatment in the existing literature. Finally, we discuss the multi-faceted communication capabilities of 6G that will contribute immensely to global sustainability. We discussed how 6G would bring about drastic changes in the business domain to orchestrate economic stability.The vision of 6G wireless networks, considering the essential requirements and comparing them with the existing generations of wireless communication networks.A comprehensive review of the 6G enabling technologies such as Pervasive AI, Reconfigurable Intelligent Surfaces, Ambient Backscatter Communication, and more.The technical challenges associated with the enabling technologies and the non-technical challenges such as social, psychological, commercialization, and health concerns towards the actualization of 6G wireless communication.New applications and use cases in agriculture, education, media and entertainment, tourism, transport, and logistics to be enabled by 6G.Harnessing the potentials of 6G to meet the UN sustainability goals and business model tailored towards attaining global economic stability.The recent trends and future research directions for 6G wireless communication. We identified some open research issues and summarized the proposed research focus.Finally, the lessons learned from the survey are delineated, and the conclusion to the paper is presented.The rest of this paper is organized as follows: There are a few related works of literature that proposed the vision, requirements, enabling technologies, and design of 6G wireless networks ,40,41,42This paper extensively considers existing research, clearly outlining the enabling technologies and the associated challenges, applications, and new applications such as the IoBNT and Digital Replica, which are not given adequate treatment in many related papers. Use cases in agriculture, education, media and entertainment, and more are discussed extensively. Apart from the technical challenges associated with the enabling technologies, this paper examines the social, psychological, and health concerns that could pose a challenge to 6G adoption. This paper also explores the recent research breakthroughs in 5G and the limitations of 5G, which make 6G a highly prospective candidate. A comparative review of some of the proposed enabling technologies, open research issues and lessons learned, and proposed future research directions are also discussed extensively.In summary, The analog wireless cellular network, which formed the first generation of wireless communication, was in use in the 1980s. This facilitated voice calls between mobile users. The Advanced Mobile Phone System (AMPS), International Mobile Telecommunications Standard (IMTS), and Point to Call formed the basis for the 1G. Additionally, some European countries adopted the Nordic Mobile Radio System (NMR). This resulted in compatibility challenges. The first-generation network was monopolized and was not affordable for many. 2G brought about high-quality, secure mobile voice and basic data services such as fax and text messaging. GSM was at the core of the 2G. It was regarded as the “Groupe Speciale Mobile”—a group of technical personnel set up by the Postal and Telecommunication Administration (CEPT) Conference to develop digital mobile communication technology . This waThe GSM architecture comprises the Mobile Station, Network and Switching Subsystem, and the Base Station Subsystem (BSS), also known as the radio network. Additionally, included is an intelligent network subsystem that enables intelligent functionality such as prepaid services and short message services (SMS). GSM utilized Frequency Division Multiple Access (FDMA) and Time Division Multiple Access (TDMA) for simultaneous communication between the subscriber and the base station . The forIn the early twenty-first century, 3G was developed as an upgrade to the features in 2G. It permitted faster data rates in the range of 300 kbps–30 Mbps and services such as video conferencing, remote supervision systems, and enabled information services. Technologies such as Wideband Code Division Multiple Access (WCDMA), Universal Mobile Telephone Service (UMTS) were key to achieving the 3G. The 3rd Generation Partnership Programme (3GPP) was formed in 1998 to oversee UMTS implementation and other enabling technology for 3G. 3GPP2 was also formed in the United States to develop global specifications for 3G systems. Critical concepts for evolution toward beyond 3G networks are presented in .Long-Term Evolution (LTE) was deployed in 2009. With the proliferation of smartphones and tablets, online gaming, and other services, 4G has been a significant success, enabling these services with its data speed of 100 Mps–1000 Mbps. Although the first release of LTE was in 2005 by 3GPP in release 6, the full development was only achieved in release 8 in 2008. Further details on the technical solutions for the 3G long-term evolution are reported in . The LTE5G commercialization started in 2019, and it opens up new use cases in the Internet of Things (IoT), immersive gaming, virtual reality, and more. 6G is expected to have a higher data rate in the range 100 Gbps–1 Tbps and latency lower than 1ms. This opens up applications in holographic communication, tactile internet, extended reality, and more. There have been different descriptions of what the 6G network should be by researchers ,79,80,816G is expected to support smart cities, the Internet of Everything (IoE) , tactileFurthermore, driving trends towards 6G are introduced in In this section, we present a robust discussion of the enabling technologies of the 6G communication system. We envision that Artificial Intelligence, which was introduced in 5G, will be further explored and central in achieving an intelligent 6G network. Reconfigurable Intelligent Surfaces will be deployed on doors, windows, buildings, and these reflect signals and help in places where maintaining Line of Sight (LoS) is tricky. The advantages of this over conventional relay systems are discussed. Cell-free Massive MIMO, TeraHertz, and Optical Wireless Technology, and more are also treated in this section. Quantum communication has been proposed, although research is in its inchoate state. This will improve the computing efficiency and security of future wireless networks. Unmanned Aerial Vehicles (UAV) and Cubesats are proposed to facilitate space communication. Some literature presents this as the Internet of Space Things ,37. ThisOver the past decade, the progress in the field of artificial intelligence (AI) has accelerated due to the introduction of deep learning (DL) and ease in its implementation ,97. ThesFurthermore, the traditional theories cannot optimally adapt to real-time fluctuations in operating conditions , non-linMachine Learning has been applied in 5G, and  classifyAdvanced machine learning techniques can be harnessed to manage big data and algorithm-driven applications. Toward this end, Zhang et al.  survey hMany challenges have been identified with the application of AI in wireless networks. Getting training data is cumbersome, and there are practically no training data to work with as we have in other fields such as natural language processing and computer vision. These data require computational and processing resources, which leads to communication costs . The sevDeep-learning-based solutions require high computational complexity, which might not fit in current mobile phones . BarringReconfigurable Intelligent Surfaces (RIS)  are enviThe metasurfaces are implemented with conventional reflect arrays ,141, liqThe spectral and energy efficiency can also be enhanced by jointly optimizing the active transmit beamforming at the AP and the passive reflects beamforming at the RIS. Therefore, RIS improves spectral efficiency . OperatiAlthough the RIS looks promising to facilitate communication beyond 5G, some challenges have been posed. In , the limDynamic modulation of RIS using low-power semiconductor elements such as PIN diode was proposed to address dynamic reconfigurability problems ,153. ThiAnother challenge associated with the RIS is estimating the channel information ,154, corModels have been proposed to resolve the challenge of channel estimation, one of which is the Ray-tracing-based methods , which wA deep reinforcement learning model was proposed in  to prediUnmanned Aerial Vehicles (UAVs), also known as a swarm of self-governing drones , are airThe Internet of Space Things, comprising of CubeSats and UAVs, is also proposed in  to enablnit cost  as they nit cost  and, in nit cost . CubeSatnit cost ,175, posnit cost , IoT [17nit cost , machinenit cost . Other anit cost . Figure Several application scenarios for Millimeterwave-empowered Unmanned aerial vehicle (mmWave-UAV) such as access point, communication terminal, and backbone link are investigated in . The worThe flying networks can be deployed to provide internet services to disaster-struck areas. It will facilitate the ubiquitous connectivity being desired in 6G networks. It is one of the major enabling technologies for achieving ultra-low latency communication . UAVs alSatellite communication will be key in actualizing 6G networks, and miniaturized or small satellites are being developed. Small satellites have a relatively low design and deployment cost. They also have lower implementation complexity. These satellites are deployed in Low Earth Orbit (LEOs), which allows them to have a low latency communication. LEO satellites are proposed in  as the mThere are different satellites based on their weights; pico-satellites, also known as CubeSats, have emerged as the most popular . HoweverThe authors in  identifiBuilding the UAVs to work in different environments by enhancing the capability of the networking protocol helps to address the issue of intermittent network changes and channel impairment . OptimizOne of the significant challenges with CubeSats and other miniature satellites is the lack of a standardized channel model . Some moRF frequency band below 6GHz has been exhausted, and there are research interests in higher spectrum. Spectral efficiency can be increased by increasing bandwidth while applying massive MIMO. This is achievable at higher frequency bands . The authors in  proposedRappaport et al.  also ideFurthermore, they also facilitate underwater communication . VLC posTHz communication has inherent short propagation capability. It becomes difficult to detect weak signals as sensitivity decreases at the THz range . At highTHzphism, a frequency-based beam spreading technique that utilizes several true-time delay (TTD) devices in a phased array antenna. This helps to improve angular coverage while maintaining the distance covered by the THz system. This encourages the adoption of phased-array-based beamforming in reducing severe pathloss. Precoding techniques such as analog beamforming, hybrid precoding, and delay-phase precoding were also proposed by the authors in [Yifei et al.  also idethors in  as proviAkyildiz et al.  considerHybridization of micro-LED matrices and CMOS driver arrays on a single chip will also be required to solve the challenges of huge matrices . As the VLC is posed with the challenge of interference with ambient light sources, and it is proposed that increase in VLC devices will result in interference between VLC devices . Signal The combination of Time Division Duplex (TDD), massive MIMO operation , denselyCell-free Massive MIMO has significantly outperformed existing small-cell systems throughput and more resistant to shadow fading correlation . MassiveOne major challenge with cell-free massive MIMO is obtaining accurate Channel State Information (CSI) ,133. TheTo improve security, Hoang et al.  suggesteMany papers addressing the vision and requirements have proposed blockchain adoption in 6G wireless networks ,81. BlocBlockchain is also being considered for the fledgling 5G communication network. Blockchain was proposed to give 5G IoT integrity, accelerated data change, lower cost, security, immutability . IntegraAlthough blockchain technology is proposed to give security and privacy to future wireless networks, the system on its own is not resistant to cyber-attacks. Security and privacy have been identified as concerns in blockchain technology . Xie et Yang et al.  also ideAmbient backscatter (AB) was proposed by  to enablM-PSK for backscattering and derived the optimal multi-level energy detector and the closed-form symbol error rate (SER). A 4PSK-AB hardware prototype that gives a data rate of 20 kb/s was developed to integrate the 4PSK-modulated transmitter, multilevel detector, and energy harvester. Recently, the issue of symbol detection in ABCS with the multi-antenna reader was addressed [Ambient Backscatter Communication (ABC) sensors were deployed to solve the problem posed by the fusion of local decisions over multiple-access fading channels in WSN, considering the IoT vertical . ABC senddressed . Leveragddressed ,224 and There is a limited coverage area for operation as backscatter transmitters need to be placed near their RF source . This meLiu et al.  identifiOne question posed by the authors in  is what Future quantum internet is proposed to be likely based on long-distance quantum optical communication suitably interfaced with solid-state nodes for quantum information processing . There aWhile channels of classical computing are well treated within the framework of classical information theory, the quantum channel is not entirely understood . ConstraEvery generation of wireless networks has facilitated new applications, and 6G is not an exception. The need for higher data rates, lower latency, high reliability, and more have given rise to the development and deployment of new wireless generation networks. In this section, we examine the applications to be facilitated by 6G. Although these or similar applications have been proposed to be enabled by 5G, 5G cannot meet the requirements to facilitate these applications seamlessly at the current development stage. Some limitations in 5G, such as scarce bandwidth and high-energy consumption, have been identified . AlthougSome of the applications to be facilitated and fully enabled by 6G are holographic communication, teleoperated driving, tactile internet, Industry 4.0, and more. New applications that were not considered in the 5G context, such as IoBNT and Digital replica, are also introduced in this paper. Holography utilizes a laser beam to produce images. This concept has been used in color motion holography , metasurWith 6G wireless networks proposed to have a data rate in the order of 1Tbps and ultra-low or non-existing latency, holographic communication will cease to be just a utopian technology limited to movies. As we go higher in the frequency spectrum, and with technologies such as VLC and more, higher data rates would be achieved. A truly ubiquitous environment empowered by real-time holograms could make smart devices appear like horse carriages. Peak data rates would reach Tbit/s in the 2030s, which will require massive bandwidths availability. The huge data rate would enable 16K video resolution in 360 degrees with a refresh rate of 240 Hz required for holographic displays . 6G is eMicrosoft developed Holo Lens, and this has stirred more research interests in this field. Projects such as Holoportation, Ada, and many more, cutting across engineering, commerce, games, etc. Spatial, a virtual communication application that uses Microsoft Holo Lens 2. This allows workers in different locations to communicate using avatars or holographic shapes of themselves. An effective holographic video conferencing enhances the borderless workplace experience where people can work from home. The holographic display has also been primarily embraced in recent times. The holographic display market is projected to reach USD 3576 million by 2020 from USD 567 million in 2013 , USD 7.66G is proposed to increase the functionality of Autonomous Driving. There is interest in teleoperated driving (or semi-autonomous vehicles) where a human controls the vehicle remotely. Teleoperated driving has been used in deep-sea and space exploration. Companies such as Ericsson and Huawei have tested teleoperation on 5G networks . TeleopeTactile internet enables haptic interaction with machines, giving rise to visual feedback and robotic control. This facilitates efficient human-to-machine interaction, machine-to-machine interaction, with key examples found in industry, robotics and telepresence, virtual reality, augmented reality, healthcare, road traffic, education and culture, and smart grid . This teResearch advances in nanotechnology and communication engineering have engendered embedded computing devices based on graphene and metamaterials. Although artificial materials  have been developed, a more biological application is preferred using biological cells and interfacing the bio-chemical interaction with the electrical domain. This is to lower the risk of exposure to toxicity associated with artificial devices. These devices can perform intra-body sensing, actuation, processing, and networking with a small size and implanted. They have a low data-storage capacity and low transmission range . The IntNevertheless, it will play a crucial role in future wireless networks. To enable this, challenges associated with IoBNT need to be resolved. Embedding with molecular communication (MC) is proposed to improve the range of transmission . HoweverThe fourth industrial revolution, also tagged Industry 4.0, is expected to enhance the computerization obtained in the third industrial revolution. Although 5G initiated Industry 4.0, 6G is expected to facilitate its full actualization. A combination of cyber-physical activities, IoT and IIoT, cloud computing, and AI will make Industry 4.0 achievable . Some teExtended reality (XR) is a term that combines VR, AR, and MR  . It takeBlockchain has been identified earlier as one of the enabling technologies for the actualization of 6G. 6G also provides an enhanced blend of massive machine type communication (mMTC) and URLLC . The relThe CRAS concept was proposed as an application of 6G in ,48. CRASWireless Brain–Computer Interaction (BCI) devices help support, enhance and generally improve human functions . This isDigital replica, also referred to as digital twin  and physThe applications mentioned above, the 5G limitations, and how 6G wireless networks will enable them are highlighted in It was shown in the preceding It has been projected that, by the year 2050, current agricultural production must increase by 60–70%  to caterThe application of IoT in the agricultural supply chain was also presented in . Some otAs a result of the COVID-19 pandemic, many schools have been forced to adopt an online training mode. There has also been growth in enrollment in Massive Open Online Courses (MOOC) in recent years, with an estimated global enrollment of 110 million in 2019. According to a survey to understand the perspective of teachers in a sample population of AR, it was shown that learning online can be enhanced by utilizing AR in training . The surThe use of holographs and XR will help to give students a better experience while learning. A good example is the training of surgeons, in which XR presents a good platform for training. We propose the application of 6G in providing remote access to surgeons in the theatre room. This widens the reach of consultants in teaching hospitals to reach more students remotely and provide professional support to students and doctors during surgery. Additionally, the UAV provides mobile ambulance access to the network, thereby allowing communication during emergencies. To actualize this, the Doppler effect from moving the UAV and ambulance will need to be tackled. This use case will benefit from the concept of high mobility hotspot introduced in . 6G netw5G is expected to double annual media revenues in the next ten years to $420 billion in 2028 , and gamMany hotels have widely adopted hotel automation based on IoT. AR use cases are also providential in improving challenges associated with accommodation, transportation, and catering solutions. A recommender system was proposed in  to aid tSome tourism companies have already adopted this in virtual tours, booking interfaces, and other travel experiences. Tourism, education, marketing are other areas where VR and AR can be adopted . DigitalSmart Logistics is one of the driving trends towards the actualization of Smart Cities, and several applications have been identified . It is pDespite the benefits 6G promises, some challenges could hamper the actualization of these networks. This paper examines the challenges of enabling technologies for the 6G networks in detail and proposes creative solutions to circumvent these challenges. It also clarifies the psychological and health issues associated with network densification and indoor wireless communication that 6G will be built. This paper categorizes the challenges based on the enabling technologies stated in Some signal processing challenges that currently stand in the way of the full actualization of 6G have been identified in the paper. The challenges are delineated in this section, considering challenges and probable solutions identified by researchers. The challenges can be classified into Channel Estimation, Hardware complexity, and Precoding. Channel Estimation challenges associated with RIS systems have been treated in this paper, and the issue of hardware complexity has been raised severally. The paper focuses on precoding in this section.Precoding is a useful technique in solving the path-loss issue in THz communication  without Social factors can make or mar the adoption of technology, and 6G wireless communication is no exception. As humans, our psychology and environment guide many of our actions. There was a hot debate that accompanied 5G implementation. It was believed in some quarters that the high-frequency spectrum is insidious to health. Some conspiracy theorists went as far as linking the 5G network to the proliferation of the COVID-19 pandemic. In this section, we critically examine the social, psychological, and health concerns. Furthermore, we examine some impending challenges that may sprout up during 6G commercialization, and suggestions were made to tackle these challenges. Considering the cost of implementing future wireless networks, it is important to convince governments and agencies that it is expedient to implement it. Despite the benefits technologies driven by 6G networks present, there have been concerns on the health risks of 5G and 6G, especially considering network densification and transmitting at a higher frequency spectrum ,48. AlthThe International Commission on Non-Ionizing Radiation Protection (ICNIRP) has recently updated their exposure guideline to abide by mobile operators and telecommunication companies. The new guideline covers higher frequency bands envisaged in 5G networks and beyond . It is c6G commercialization challenges were keenly discussed at the 6Genesis Flagship Program (6GFP) launched in Finland in May 2018. The 6GFP consortium comprises academia, research centers, institutes, industrial and business partners, and coordinated by the University of Oulu in Finland. The program is the first to focus on 6G research globally . The DirThere has been limited literature on the potential commercialization challenges of 6G. Although the deployment of 6G is expected to commence in 2030 , it is pThe use of UAVs and advanced radio techniques, exploitation of solar-powered energy-efficient devices, reusability of network components and functions, and deployment of commodity hardware were identified as some of the pillars to actualize connectivity in rural areas . HoweverAlthough the mmWave was presented as the enabling spectrum for 5G, early deployment of 5G has been on the sub-6GHz spectrum. Early 6G deployment may not be deployed on THz immediately at the point of deployment. The early adoption of sub-6GHz in 6G was suggested in . It is, In this section, we discuss 6G sustainability and business model. First, we present a brief discussion in The 5G networks have drastically resolved several social issues inherent in 4G wireless networks. For example, environmental protection and education have received remarkable improvements in the 5G era. However, the problems of connectivity and urbanization remain. No doubt, 6G will usher in a great sigh of relief. User-experienced-based hyperdata connectivity will be ubiquitous and regional barriers will be broken to achieve a truly borderless society ,302. The6G will also enable context-aware environment sensing and indoor localization to aid online monitoring and support the massive uplifting of the SDGs ecosystem. A summary of the set of KPIs for all 17 SDGs, including probable use cases, is presented in . To provGiven the recent global financial crisis, there is no denying the fact that the existing corporate business models had a significant impact on the sustainability of the global economy and society ,309,310.6G will bring about a dramatic change in the business arena. The future of business will be characterized by a seamless and automated collection of market data from humans and the dynamic business environment. 6G will provide a user-friendly platform for intelligent analysis of big data for high-end products and specialized services. These products and services would be designed to be highly sustainable and well-tailored to address the peculiar needs of the consumers in rural and urban geographies. Additionally, 6G will aid crowdsourcing and enhance cutting-edge distribution platforms to support sharing sustainable business models to accelerate the equitable distribution of resources. Recently, the choices for developing the first-class sustainable 6G business future for all the participants in the future 6G business were recapitulated by . These uThis section considers some recent trends in 6G applications, such as Holographic communication, space communication, and more. We have also identified areas where further research is needed. We have considered some research propositions by several researchers hoping this will stimulate research and facilitate the progress, development, and rapid implementation of 6G wireless communication. We conclude the paper with a summary of key take-away lessons for further research and development in 6G wireless communication.China launched the first 6G satellite to space in November 2020. The satellite uses high-frequency terahertz waves for data transmission. Although the launch is just a trial, and it is not sure if it will be in the final 6G standard, this has ushered in the 3D architecture of terrestrial, space, and underwater communication, kick-starting transmission on space. There is an ongoing development of 6D Holographic optical field technology. This will be enabled by the exigent specifications of higher data rate and low latency to be facilitated by 6G. This technology presents a new and desirable user experience in media and entertainment. Security has been identified as a challenge in the adoption of the Internet of Bio-Nano Things. The authors in  proposedPervasive AI is crucial in actualizing intelligent future wireless networks. However, there is a challenge of having energy-efficient hardware at the mobile unit, allowing users to experience high-speed applications such as extended reality, fully autonomous systems, and more. Therefore, further research is needed to produce hardware that will be compatible with 6G. These devices are desired to be energy efficient. This keeps in play the vision to have longer battery life. Security and trust of wireless networks is also an issue which 6G is expected to combat. There is a need for more research on quantum communication. As stated earlier in this paper, technologies such as Quantum communication, Internet of Bio-Nano Things might not be mature enough to enable 6G. Still, they will be key future wireless networks. Quantum communication not only improves security but also improves computational efficiency. Space communication has been explored in this paper. If this is incorporated with terrestrial and underwater communication, the vision of a true ubiquitous communication network will be achieved. Saeed et al.  envisageSaad et al.  opined tIn this section, we have identified and summarized lessons learned from this research work. We believe these lessons are crucial and will guide researchers on progressing 6G research.Lesson 1: Comparing the Key Technologies that will facilitate the actualization of 6G.It has been established that Terahertz communication and VLC will give a higher data rate than the one obtainable in 5G networks. Cell-free massive MIMO presents a new concept that eliminates cells in communication and improves user experience. UAVs and CubeSats, which form the Internet of Space Things introduced in , and undLesson 2: 5G is limited, and 6G is proposed to provide requirements that will be compatible with emerging applications and services.Current 5G systems do not have the bandwidth to support a fully immersive XR experience and high definition holographic communication. Applications such as Tactile Internet, Wireless Brain–Computer Interface also require high reliability and ultra-low latency, which 5G cannot provide. Additionally, needed is a very high data rate in the order of 1Tbps with a latency <1 ms, making delay imperceptible to humans. These will be provided by 6G. Achieving this enables new use cases in agriculture, education, media and entertainment, tourism, and logistics. Additionally, it has been established that the sub-6GHz band is crowded. There are research interests in TeraHertz spectrum communication. This will provide a new spectrum and enable higher data rates, which are desirable in 6G. Optical Wireless Technology such as Visible Light Communication and Free Space Optics also need to be explored.Lesson 3: Compatibility at the hardware level is still a major challenge as many UE are currently not 6G compatible.Artificial Intelligence is proposed to enable wireless networks to be intelligent entities. However, this casts a toll on the energy requirement at the mobile unit, as high processing power is required to process a large amount of data and the AI algorithms. Additionally, there is a need for new chips for TeraHertz communication. Wireless Network on Chip (WNoC) has been introduced in , but furLesson 4: Will there be a complete overhaul of the backhaul of present wireless networks, or will there be new Infrastructure? Not certain.It is not yet clear if there will be a complete overhaul of existing wireless networks with a new architecture for 6G. However, there will undoubtedly be a need for more infrastructure, especially RIS, UAVs, CubeSats, which are yet to be widely adopted. Massive MIMO previously deployed in 5G will be further explored to incorporate a cell-free massive communication network. A 3D network architecture that combines satellite, UAV, and terrestrial networks is proposed to facilitate ubiquitous communication. This will bring about space and terrestrial communication. It is also crucial to incorporate underwater communication. It is worthy to note at this juncture that it will be desirable to incorporate the existing architecture, especially those of the recently commercialized 5G. This enables a network that is not just performance efficient but cost-efficient.Lesson 5: 3CS .6G has been proposed to be a multi-purpose system that combines communication, computing, control, and localization . The autLesson 6: Haptics will be more prominent.Haptics present a form of communication using touch. Haptic devices have a unique bi-directionality feature that allows them to communicate with the brain, i.e., bi-directional communication with the brain. Teletouch facilitated by Haptics technology will remake the internet into allowing users to move distant objects and experiencing instant tactile feedback. Upon the wide adoption of haptics, it has been proposed to be the end of the smartphone era , a new eLesson 7: Industry 4.0 will be facilitated by CRAS, smart logistics, precision agriculture, smart cities.There will be a pervasive application of AI and automated control systems. This will open up applications such as CRAS that will improve industrial processes and products effectively. Industry 5.0 will be more user-centric with the personalized manufacturing process. Holographic communication, Multisensory XR, Digital Twin, and more will facilitate the actualization of smart cities. This will also bring about an upgrade in the media and entertainment industry. There will be a better user experience in online gaming through extended reality, tactile devices, and more. New use cases in smart logistics, precision agriculture, and more have been introduced in this paper, and these are expected to drive massive industrialization. These applications and use cases make the actualization of 6G desirable.Lesson 8: Security, a desirable feature of 6G, will be provided by blockchain and quantum communication.There are research interests in quantum cryptography and quantum machine learning. This is expected to make future wireless networks secured. However, quantum communication research has not received as much attention as other enabling technologies; thus, casting doubts on its maturity in 6G deployment. Therefore, there is a need for more research focus on quantum communication. Blockchain is another technology that will improve the trust and security of future wireless networks. This is a distributed ledger technology with decentralized control. Artificial Intelligence will also play a role in detecting threats in wireless networks, thus creating a secure and self-sustaining network.Lesson 9: Need for a new networking protocol.There is also a need for new networking protocols or an upgrade to the existing ones to be compatible with the new technologies such as the THz frequency spectrum, which are enablers of 6G. As stated earlier in this paper, communicating at a higher frequency spectrum is prone to high path loss. Therefore, there is a need for hardware to improve the transmission range of THz communication. There is also a need for a robust system and algorithm for handover management in UAV/CubeSat communication. It is as well crucial that these hardware architectures are low-cost and energy-efficient. Additionally, as stated earlier, compatibility with existing infrastructure is desirable.Lesson 10: Multiplexing methods.Multiplexing techniques such as Orthogonal Frequency Division Multiplexing (OFDM), Generalized Frequency Division Multiplexing (GFDM), Filter Bank Multicarrier (FBMC), Spatial Multiplexing, and more, are proposed in 5G. Further research is needed to ascertain how these multiplexing methods will be crucial in actualizing the desirable 6G networks. Spectrum and infrastructure sharing is also desirable to maximize capabilities, and CR and Blockchain are some of the technologies proposed. Further research is needed to achieve this. Generally, there is a need for new protocols and standards for 6G to enable standardization and compatibility. Additionally, software-defined networking (SDN) needs to be explored to resolve protocol incompatibility.Lesson 11: Need to provide pragmatic solutions to the vast sustainability problems by adopting innovative and sustainable business models.Sustainable business is key to knowledge creation to drive human empowerment, technology acquisition and transfer, economic stability, entrepreneurship and innovation, ecological reconstruction, and democratization of government institutions. However, most current business models are not sustainable. There is a need for adaptive and innovative business models to regulate the market forces to achieve global economic stability. Ultimately, such business models will accelerate productivity and rapid economic growth in rural environments towards achieving the UN sustainability goals.This paper attempted to discuss how the 6G wireless network will enable cutting-edge applications, which the existing 5G has not seamlessly facilitated. The enabling technologies for 6G wireless networks are discussed in detail and contrasted with the existing 5G technology. The challenges which pose as barriers to the actualization of 6G wireless communication are emphasized. The accompanying social, psychological, health, and commercialization challenges are discussed. New use cases of 6G in agriculture, education, media and entertainment, tourism, transport, and logistics, are broached. Channel estimation, security, underwater communication, and more require further research to guarantee the envisioned ubiquitous connectivity in the 6G era and beyond. The multi-faceted 6G wireless communication capabilities in accelerating the United Nations Sustainable Development Goals to drastically alleviate poverty, promote an equitable and fair distribution of scarce resources, improve healthcare delivery, and maintain global economic stability are discussed extensively. Finally, we have given a concise but more explicit vision of what 6G will be, provide an up-to-date review of the emerging trends, assess the potential challenges envisioned in 6G wireless network deployment, and stimulate research initiatives to tackle these challenges for societal advancement.


Therefore, the aim of this study was to determine the influence of somatic cell counts (SCC) on the colostrum immunostimulating and chemical components. The experiment was conducted on an experimental organic dairy farm in which a herd of approximately 250 cows was kept in a freestall housing system, with the average performance exceeding 6,000 kg of milk per lactation. Colostrum and milk samples were taken individually from each cow seven times during the experiment: from the first to second day after calving–twice per day, and from the third to fifth day after calving–once per day. Therefore, after preliminary analyses, the cows were divided into two groups based on the cytological quality of their colostrum at the first collection: 1. SCC ≤400,000 cells/ml , 2. SCC ≥ 400,000 cells/ml . The study found almost double the concentration of immunoglobulins and essential fatty acids in first milking colostrum in the GCC group than in colostrum from the LCC group. In addition, an increase in the concentration of lysozyme in first milking colostrum was associated with a decrease in the concentration of immunoglobulins. In addition, the increase in the level of lysozyme was associated with a decrease in the concentration of immunoglobulins. In conclusion, the SCC of first milking colostrum can be used as an indicator of colostrum quality.The impact of cow mammary gland diseases on the quality of colostrum is not conclusively defined; research results are conflicting. However, it is widely believed that  The most critical time for calf health is the first two weeks of life, with high mortality rates associated with the feeding of poor quality colostrum, poor environmental hygiene, and digestive disorders . Calves S. aureus strains [Lactobacillus casei on the surface of the mucosa and stimulates their growth, whereas it reduces the development of pathogenic bacteria from the genera Helicobacter, Shigella, Salmonella, and Pseudomonas [E. coli membrane inhibited the attachment of proline to its membrane. The properties of lactoferrin can be further enhanced by their ability to act synergistically with lysozyme [Vibrio cholerae and E. coli by swelling and dissolving their cell structure. In addition, LF allows reducing doses of administered antibiotics [Staphylococcus epidermidis, the administered dose of vancomycin–an antibiotic used to fight this strain–could be reduced twice by lysozyme addition. Likewise, when added to penicillin, it increased its activity even four-fold against S. aureus [Candidia albicans and C. krusei), which were treated with lactoferrin free of iron, changed the structure of the surface by creating blisters on it with leakage of proteins [Colostrum is a rich source of immunity-enhancing components, including immunoglobulins (Ig), lactoferrin (LF), lysozyme (LZ), and polyunsaturated fatty acids (PUFA) . Omega-3 strains . ALA supudomonas ,10. Lactudomonas . In contudomonas . Gram . During the experiment, the cows were under veterinary care and remained healthy for the duration of the study and did not show any disorders and diseases that could generate an immune response .The experiment was conducted on an experimental organic dairy farm in which a herd of approximately 250 cows was kept in a freestall housing system, with the average performance exceeding 6,000 kg of milk per lactation. Dry cows were fed according to the Nutrient Requirements Committee. Dry cows’ requirements, daily ration, as well as nutrient balances are presented in Tables Forty multiparous (in second lactation) Polish Holstein-Friesian cows were selected for the experiment. An additional criterion was the production of at least 2 L of colostrum in the first milking.The first sample of colostrum was collected up to two hours after calving. Samples were taken individually seven times during the experiment: twice a day on the first and second day after calving, and once a day from three to five days (using the milking machine). The colostrum yield was medium (3–6 kg) for all cows, and foremilk was stripped out of the gland prior to sample collection. Colostrum samples and milk (250 ml) were placed in sterile bottles, preserved with Milkstat CC , and transported to the Warsaw University of Life Sciences.After preliminary analysis of colostrum SCC distribution, cows were divided into two groups based on the SCC of the first sample collected after calving: 1) SCC ≤400,000 cells/ml ; LCC (n = 22), and 2) SCC ≥400,000 cells/ml ; GCC (n = 18 cows). It should be noted that the colostrum samples met the microbiological quality requirements for bacterial contamination .The microbiological quality of colostrum was determined by Bacto-Scan .The basic chemical composition of the colostrum, i.e., fat, protein, casein, density, and lactose content, was determined by automated infrared analysis using a Milkoscan FT– 120 analyzer .Cytological quality  was established using a Somacount 150 analyzer .Concentrations of lactoferrin and lysozyme were determined using an Agilent 1100 Series RP-HPLC  according to the methodology described by Puppel et al. . SeparatConcentrations of immunoglobulins were determined using an Agilent 1100 Series RP-HPLC  according to the methodology described by Puppel et al. . Separattrans-esterification method PN-EN ISO 5509:2000 [Fatty acid methylation was carried out with the 509:2000 . Content509:2000 . Each peThe experimental data were statistically analyzed by two-way ANOVA according the model presented below using SPSS 23 . To detei is the fixed effect of the colostrum sample (I = 1 − 7), Bj is the fixed effect of the SCC level, Ai × Bj is the interaction between subsequent colostrum sample effect and SCC level, and eijk is the residual error.The statistical model was:Auldist and Hubble  report tBovine immunoglobulins include IgG (G1 and G2), M, and A, with IgG accounting for 65–90% of total colostral immunoglobulins . ColostrThe quality of colostrum varies, with that variability being determined by animal and environmental factors ,34,35. TFigs The fat in the colostrum is an important element of a calf’s diet by providing the energy necessary to maintain body heat, and also by acting as a precursor for the synthesis of certain enzymes and hormones ,31,35. TThere is also a different group of proteins which are very significant in terms of the colostrum’s bacteriostatic and germicidal properties, that includes the non-specific antibiotic agents lysozyme and lactoferrin. Lysozyme, also known as muramidase, is a hydrolytic enzyme , which oThe lactoferrin (LF) content in bovine colostrum ranges between 0.34 and 4.96 g/L ,44,45. DCyclooxygenases and lipoxygenases from PUFAs produce both pro-inflammatory molecules (prostaglandins and leukotrienes), and anti-inflammatory molecules (lipoxins and resolvins) . TherefoKisza and Botura  demonstrcis-9 trans-11) inhibits prostaglandin-E2 synthesis [Conjugated linoleic acid  compared with the LCC group . It should be emphasized that the quality of colostrum varies, with this variability being significantly influenced by the level of somatic cells. Therefore, it can be concluded that SCC can be used as non-invasive indicator of colostrum quality.S1 File(PDF)Click here for additional data file.


Neuropeptide Y (NPY) and peptide YY (PYY) are involved in metabolic regulation. The purpose of the study was to assess the serum levels of NPY and PYY in adolescents with anorexia nervosa (AN) or obesity (OB), as well as in a healthy control group (CG). The effects of potential confounders on their concentrations were also analysed. Eighty-nine adolescents were included in this study . Anthropometric measurements and psychometric assessment of depressive symptoms, eating behaviours, body attitudes, and fasting serum levels of NPY and PYY were analysed. The AN group presented severe depressive symptoms, while the OB group held different attitudes towards the body. The levels of NPY were lower in the AN and OB groups as compared with the CG. The PYY levels were higher in the OB group than in the AN group and the CG. The severity of eating disorder symptoms predicted fasting serum concentrations of NPY. Lower levels of NPY in AN, as well as in OB suggests the need to look for a common link in the mechanism of this effect. Higher level of PYY in OB may be important in explaining complex etiopathogenesis of the disease. The psychopathological symptoms may have an influence on the neurohormones regulating metabolism. Eating disorders (EDs) and obesity (OB) are distinct conditions with several overlapping biopsychosocial risk factors, such as ethnicity, personality traits, adverse events, and neurobehavioural disturbances ,2. GlobaThe aetiology of both AN and OB is still poorly understood, and treatment programmes leave a lot to be desired. In recent years, several peptides and hormones crucial for maintaining homeostasis through the regulation of appetite and metabolism have been identified. Many of them are produced and interplay in the brain, fat tissue, or digestive system. Moreover, some of them act in the limbic system and cerebral cortex, regulating perception, mood, motivation, and other food-related processes ,11,12. TPYY is secreted mainly in the gastrointestinal system, by L-type neuroendocrine cells located in its lower part and by the endocrine cells of the pancreas ,14,15,16In contrast, NPY is a peptide produced and acting mainly in the brain. NPY and its receptors are widely expressed in the cerebral cortex, thalamus, hippocampus, amygdala, and basal ganglia ,23,24. HIt has been postulated that both neuropeptides NPY and PYY interplay in homeostasis regulation. Thus, in NPY/PYY-knockout mice, lower food intake and impaired insulin action have been observed ,31,32. FHuman studies on NPY and PYY in OB and AN are inconclusive. Most of them have focused on the role of NPY in overweight subjects. They have proven that the NPY gene is associated with increased body weight and that NPY activity is increased in OB . Less isThere is a gap in the knowledge of hormonal appetite responses in adolescents with either OB and AN. Studies in this age group are crucial because this is the time when the first symptoms of these disorders appear and when significant neuroplastic processes occur. Therefore, the purpose of the present study was to assess the serum levels of NPY and PYY in adolescents with OB or AN, as well as in a healthy control group (CG). A secondary goal was to test for the effects of potential confounders on the concentrations of NPY and PYY, including age, body mass index (BMI), and glucose and insulin levels, and to explore the impact of eating disorders and depressive symptoms on these neuropeptides in adolescents across the weight spectrum. We expected that the concentrations of NPY and PYY might be associated with homeostatic regulation factors such as glucose or insulin, and also with the emotions, attitudes, and behaviours connected with food intake.Eighty-nine adolescents (11 boys and 78 girls) were included in the study. Thirty of them were admitted to the Department of Pediatric Diabetes and Obesity because of obesity (OB group). Thirty girls were admitted in the acute phase of anorexia nervosa (AN group) to the Department of Child and Adolescent Psychiatry. The remaining 29 subjects were recruited among middle school students (CG). Patients with AN were hospitalised for the first time and had symptoms of the disease for less than a year. Diagnosis of the restrictive type of AN was made according to the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) and 5th revision of Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The inclusion criteria for AN and OB were age- and gender-adjusted BMI percentile of 5 and 95, respectively. The exclusion criteria for all participants, including CG, were the occurrence of any psychiatric disorders based on the interview conducted by a specialist in child and adolescent psychiatry, chronic somatic illnesses and laboratory abnormalities not related to OB or AN, chronic medication use, and dietary supplement intake.2), and the percentage of ideal body weight (%IBW) as a ratio of actual to ideal body weight (IBW) × 100%, where IBW (kg) = height (cm) − 100 − {[(height (cm) − 150)]/2} according to Lorentz’s formula [All patients had the following checks within two days of admission: Height and weight were checked, psychometric evaluation was carried out, and 15 mL of blood was obtained. BMI was calculated as the ratio of body weight (kg) to height squared (m formula .The Beck Depression Inventory (BDI), the Body Attitude Test (BAT), and the Eating Attitudes Test (EAT-26) have high reliability and validity and are widely applied to assesses specific psychopathological symptoms in adolescents ,47,48,49The CG also underwent a physical and mental examination, anthropometric measurements, psychological assessment (except the BAT), and laboratory tests. The research protocol was approved by the Poznan University of Medical Sciences Bioethics Committee (265/18 and 295/18). All procedures were conducted according to the 1964 Declaration of Helsinki. Consent was obtained from all participants and their guardians.g for 15 min at 4 °C, aliquoted into Eppendorf tubes, frozen at −70 °C, and assayed afterwards.Venous blood was collected on morning admission (8:00–9:00 a.m.) from fasting  AN, OB, and CG subjects. Serum was immediately separated from the blood by centrifugation at 1000× Quantitative NPY and PYY tests were performed using a commercial one enzyme-linked immunosorbent assay , following the manufacturer’s instructions.The measurement range of the kit was 78–5000 pg/mL for NPY and 6.25–400 pg/mL for PYY. The minimum detectable dose of general NPY is typically less than 32 pg/mL, and for PYY, less than 3.1 pg/mL. Optical density was read via a spectrophotometric plate reader (Biochrom Asys UVM 340 Microplate Reader) at a wavelength of 450 ± 10 nm. Every assay was performed twice, and the mean value of the two assays was used for statistical evaluation. A four-parameter algorithm (four-parameter logistic) was used to assay the concentration in the tested samples.The analyses were carried out in the PQStat program, version 1.8.0.352. The data are described as arithmetic means ± standard deviation (SD). The results are also presented as boxplots.The normality of the distribution was tested by the Shapiro–Wilk test. When the data distribution differed significantly from the normal distribution, the groups were compared by the Kruskal–Wallis test and Dunn’s multiple comparison test with Bonferroni correction, or by the Mann–Whitney U test, depending on the number of compared groups. For variables with a normal distribution, the ANOVA test for independent variables and Tukey’s HSD multiple comparison test were used. The effect sizes for each comparison were also calculated.The impact of potential confounding variables on the NPY and PYY levels were analysed in all included adolescents across the weight spectrum (AN + OB + CG). For this purpose, log-transformation of the analysed variables was conducted due to the presence of outliers and non-normal distributions. However, the data remained non-normal for most of the variables. Therefore, generalised linear models were used to perform the analysis. A significance level of 0.05 was used for the statistical analyses.p < 0.001). The OB group was statistically significantly younger than the CG and the AN group; however, there was no difference between the CG and the AN group. As expected, the AN and OB groups and the CG differed significantly in terms of BMI (p < 0.001) and percentage of ideal body mass (%IBW) (p < 0.001).The demographic characteristics of all participants are presented in p < 0.001), but there were no statistically significant differences between the AN and OB groups (p = 0.661). However, the OB group and the CG differed significantly (p = 0.006) (p < 0.001) (As shown in = 0.006) . The mea< 0.001) .p < 0.001) and the OB group (p = 0.040), but there was no statistically significant difference between the OB group and the CG (p = 0.205). Patients with OB obtained statistically higher total BAT scores than the AN group (p = 0.010). They also differed in two subscales, i.e., the negative appreciation of body size (p = 0.003) and the lack of familiarity with one’s own body (p = 0.028). There were no significant differences in the total EAT-26 score among the AN and OB group and the CG . However, on the dieting subscale, there were significant differences both between the OB and AN groups (p < 0.001) and between the OB group and the CG (p < 0.001). Furthermore, in the oral control subscale, there was a significant difference between the AN and OB groups (p < 0.022).As presented in p = 0.012) but not PYY. However, age, BMI, and serum fasting glucose and insulin levels were not associated with NPY or PYY.The findings of the regressions assessing age, BMI, and fasting serum glucose and insulin, as well as the selected psychopathological symptoms, as potential confounders of the fasting serum concentrations of NPY and PYY in adolescents across the weight spectrum are shown in Patients with OB or AN and healthy subjects under the age of 18 were enrolled in the present study. They did not differ in height, but because of their diagnoses, they differed in body weight, BMI, and percentage of ideal body weight. Furthermore, they differed in the intensity of some psychopathological symptoms. Patients diagnosed with AN presented significantly higher results in the BDI than the CG and the OB group, which is congruent with reports that up to 70% of patients with AN have comorbid depressive symptoms.Subjects with OB scored higher than the AN group in the BAT scale, and the differences were mainly in two subscales, i.e., negative appreciation of body size and lack of familiarity with one’s own body. The higher results in the BAT in the OB group could be influenced by the devaluation and social stigmatisation of obesity ,54, whicp = 0.059). However, significant differences were observed in the subscales. Patients with AN were characterised by a greater intensity of oral control symptoms, and OB subjects by greater intensity of diet symptoms, which is congruent with the clinical observations and previous studies [However, it is more likely that AN patients’ self-assessment results were influenced by the denial of the disease symptoms, as reported in previous studies ,56. Ther studies ,58. ThusNumerous studies have shown that NPY levels are rising due to a lack of food, which, in turn, leads to maintaining the homeostatic balance by reducing energy expenditure, stimulating appetite, and increasing food intake ,60,61. NThe adolescent patients with increased body weight included in the present study had reduced fasting serum NPY levels as compared with healthy individuals. These results are congruent with the studies conducted by Saranck and Lou ,68 amongHowever, the reduced serum NPY levels in the recruited OB patients could be an adaptive mechanism for increased food intake. Furthermore, this effect may be mediated by leptin, which inhibits NPY and is elevated in obesity. Therefore, it seems necessary to conduct research that could explain the causes of this phenomenon.The adolescent patients with decreased body weight had also reduced fasting serum NPY levels as compared with healthy individuals. Previous studies have shown conflicting results, for example, NPY concentrations have been reported to be decreased , increasPYY is a potent anorexigenic agent. It has been suggested that peripheral PYY acts as a satiety signal, regulating the termination of individual meals, partly by reducing the production of the hunger-stimulating peptide ghrelin. The results obtained in the patients with AN confirm previous reports, i.e., the serum fasting PYY concentrations were not significantly different from those of the healthy volunteers ,80,81,82The fasting serum PYY levels were higher in OB adolescents, which is congruent with the research conducted by Patel . HoweverThe severity of eating disorder symptoms measured with the EAT-26 scale predicted the concentration of NPY in adolescents across the weight spectrum. The neural neuropeptide Y receptor system might be involved in the processes connected with eating, because the localisation of its receptors overlaps with the neural networks engaged in cue-conditioned eating in limbic and cortical areas . To the p = 0.059). In previous studies, adolescents with higher scores in BDI had lower plasma neuropeptide Y levels. The NPY receptors in the hippocampus, cerebral cortex, and amygdala are essential for NPY regulation of anxiety, reactivity to stress, cognitive processes, and depression [The severity of depression symptoms measured with the BDI scale did not predict the NPY concentration in all of the included participants, although the results were at the borderline of statistical significance (pression . Animal pression , and intpression ,103. A mpression . It has pression ,105. NPYpression . TherefoNPY and PYY were not related to age, BMI, or fasting serum of insulin and glucose in adolescents across the weight spectrum. This is congruent with many previous studies conducted among healthy people, as well as those suffering from some somatic diseases ,108,109.The authors of the present study are aware of its limitations and recall the most important of them. The number of considered variables was quite large, which reduced the power of each analysis. The healthy controls were not issued the Body Attitude Test. However, we compared the results between the AN and OB groups, and since they seemed interesting, we considered presenting and discussing them. Moreover, we did not use BAT in the confounding variables analysis. The subjects included in the study were instructed to eat their last meal 12 h before the test. We did not use any additional methods to validate the fasting state, which may have diluted the findings. However, they were also not used in the above discussed research. While interpreting the results of this study, it should be remembered that the level of peripheral peptides does not have to reflect their central activity. Moreover, the aetiology of anorexia nervosa and obesity is complex, and only single factors in the entire complex network of relationships were analysed. Furthermore, it is difficult to determine which of the alterations in protein levels are primary and which are secondary to the changes in body weight, as well as what their final role in etiopathogenesis is. Therefore, continued follow-up studies on a larger group of adolescents with AN and OB after body weight normalisation are strongly recommended. It would also be valuable to compare NPY and PYY levels across the whole spectrum of ED, including patients with bulimia nervosa and binge eating disorders. In OB and AN, circulating protein levels could be decreased, which should be considered in further analysis.The fasting serum levels of neuropeptide Y were decreased in adolescent patients with anorexia nervosa, as well as in those with obesity. This suggests the need to look for a common link in the mechanism of this effect, despite the opposite metabolic status in such different groups of patients. The right direction of further research should be taking into consideration additional confounding variables, including those related to the mental state of the patients.Adolescent patients with obesity, but not with anorexia nervosa or healthy patients, had increased fasting serum concentrations of peptide YY. This is interesting, especially since other gastrointestinal peptides are also altered in this condition and are used in the treatment; therefore, more studies on PYY are needed.Correlations between the centrally produced neuropeptide Y and the severity of eating disorder symptoms require further study in this area. We suggest that psychopathological symptoms have an influence on the neurohormones regulating metabolism. This might be crucial for therapeutic interventions in both anorexia and obesity.


The purpose of our study is to build nomograms for predicting the possibility of lung metastasis (LM) and bone metastasis (BM) in patients with intrahepatic cholangiocarcinoma (ICC).  1527 patients diagnosed with ICC between 2010 and 2016 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable logistic regression analyses were used to recognize the predictors of LM and BM, respectively. Then two nomograms were established. We applied the C-index, calibration plot, receiver-operating characteristic (ROC) curve, and decision curve analysis (DCA) to evaluate the novel nomograms. The maximum values of the Youden indexes from the ROC curves were utilized to select the cutoff points of the nomograms. The Kaplan–Meier survival curves were used to evaluate the effect of chemotherapy in different groups. The bootstrap resampling method was chosen for internal validation.  Five predictors for LM and three predictors for BM were identified, and two nomograms were constructed. The nomograms had high values of C-indexes, reaching 0.821 (95% CI 0.772–0.871) for LM and 0.759 (95% CI 0.700–0.818) for BM. C-indexes of 0.814 for LM and 0.749 for BM were also observed in internal validation. The calibration plots, ROC curves, and DCAs exhibited favorable performances for predicting LM and BM. The cutoff points of total points in nomograms were 108 for LM and 144 for BM, which could distinguish between high-risk and low-risk groups for LM and BM. Chemotherapy is suggested to undergo for patients in high-risk groups.  The nomograms could assess the possibility of LM and BM in ICC patients and determine the optimal treatment. Intrahepatic cholangiocarcinoma (ICC) originates from the epithelial lining of the intrahepatic bile duct, which is the second most universal primary liver cancer –3. ThougICC is a lethal disease which has an extremely poor prognosis, with a 5-year survival rate ranging from 15–40%. Surgical resection remains the only potential curative treatment. However, only 30–40% of ICC patients are potential to undergo radical surgery, and the postoperative recurrence rate is high, which ranges from 40% to 80% . In addiUp to now, a model that preliminarily finds out whether patients with ICC are at high risk of LM and BM does not exist yet. A nomogram is a kind of dependable graphical math model that is used to exactly predict a specific end event in combination with the related risk factors of tumor development , 17. TheCancer Institute- (NCI-) initiated registry of cancer incidence and survival rates in the United States from 1975 to 2016. We got the permission from SEER to access the research data in November 2018 for analysis (Username: 14376-Nov2018). We used SEER∗Stat software version 8.3.6 to extract patients diagnosed with ICC between 2010 and 2016 from the SEER database. The SEER database is publicly available, and all patient data have been unlabeled, so informed consent from the institutional review board is not required for this research.We analyzed the Surveillance, Epidemiology, and End Results (SEER) database, a National Cancer (AJCC) T stage and 7th AJCC N stage.The retrospective population study cohort included the following patients with international tumor classification, histology code ICD-O-3): 8160, and the ICD site code: C22.1. The exclusion criteria of this study were listed as follows: : 8160, a patientsn (%) for categorical variables. Univariate logistic regression analysis was applied to select the associated risk predictors of LM and BM. Multivariate logistic regression analysis was further utilized to define the independent risk predictors of LM and BM. We also calculated the odds ratios (OR) and the 95% confidence intervals (CI) of them to compare the risk levels of the predictors.Patient characteristics were summarized as the C-indexes in addition with receiver operating characteristic (ROC) curves were used to assess the discrimination. The cutoff values of the total scores from the nomograms were calculated according to the maximum values of the Youden index for the ROC curves. Sensitivity and specificity, positive predictive value, and negative predictive value were also displayed. Low-risk groups and high-risk groups of patients were divided by these values. In order to estimate the predictive accuracy and bias, calibration curves with 1,000 bootstrap resampling were conducted. The decision curve analyses (DCA) were utilized to evaluate the clinical use of nomograms. For internal validation of the novel nomograms, we used a bootstrap resampling method with 500 repetition. The Kaplan–Meier survival curves of the high-risk and low-risk groups for LM and BM with the Log-Rank test were plotted to compare their overall survival. Furthermore, the Kaplan–Meier survival curves of patients with or without chemotherapy in the high-risk and low-risk groups were plotted, respectively.Based on the independent predictors of LM and BM searched from the multivariate logistic analysis, two nomograms were constructed. To further evaluate the benefits of the novel models, R software, version 3.6.1 (http://www.r-project.org/). The p values <0.1 for univariate logistic regression analysis and <0.05 for other analyses were considered statistically significant.The statistical analysis of this study was performed using After screening with the exclusion criteria of our study, a total of 1527 patients with ICC were involved. Among them, 82 people had LM and 70 had BM. The detailed process of inclusion and exclusion is shown in p = 0.002), histological grade , N stage , tumor size , and intrahepatic metastasis . In addition, three significant variables were actually picked out for BM: gender , tumor size , and intrahepatic metastasis . The results of logistic regression analyses for LM are shown in To filter risk factors of LM and BM for ICC patients, the univariate logistic regression analysis was performed. There were six clinicopathological variables related to LM and five clinicopathological variables related to BM. The multivariate logistic regression analyses were used to analyze these variables. After gradually removing variables, five significant variables were actually picked out for LM: gender . According to these nomograms, the probability of LM and BM could be easily calculated, by summing up the total scores of each predictor as there were parallel lines below the figures whose scales had a linear relationship with each other. This result implied that we could predict the possibilities of LM and BM when a patient's clinicopathologic characteristics were given explicitly.Two nomograms were constructed to predict the possibility of LM and BM in patients with ICC based on the predictors searched from multivariate logistic analyses Figures . IntraheThe nomograms demonstrated good accuracy, with C-indexes of 0.821 (95% CI 0.772–0.871) for LM and 0.769 (95% CI = 0.737–0.801) for BM. We performed the calibration of the LM and BM nomograms internally with 1000 times bootstrap sampling. The calibration curves of the LM and BM risk-predicting nomograms demonstrated good agreement between prediction and observation Figures . Then, tp < 0.0001). The optimal cutoff value of LM had a sensitivity of 78.0%, a specificity of 75.1%, a positive predictive value of 15.1%, and a negative predictive value of 98.4%. Similarly, the optimal cutoff value of LM had a sensitivity of 75.7%, a specificity of 68.8%, a positive predictive value of 10.4%, and a negative predictive value of 98.3%. Furthermore, the Kaplan–Meier survival curves of patients in the high-risk groups and low-risk groups were plotted . The median OS was 13 months for patients with low risk of LM and 7 months for those with high risk of LM. The median OS was 14 months for patients with low risk of BM and 7 months for those with high risk of BM. These results indicated that our nomograms could stratify the risk of LM and BM in patients with ICC and preliminarily predict survival of these patients.We obtained the cutoff values of 108 for the LM nomogram and 144 for BM nomogram from the maximum values of the Youden indexes of the ROC curves. All ICC patients were divided into a low-risk group and a high-risk group for LM  and BM , respectively.  Figures . The Logp < 0.001) (p < 0.001) (p = 0.42) (p = 0.46)  of patients with or without chemotherapy in high risk and low risk of LM and BM patients with ICC. The results showed that ICC patients with high risk of LM who underwent chemotherapy had better survival rates than those who did not  . Similar< 0.001) . In cont = 0.42) . ICC pat = 0.46) . These rIt is a matter of fact that distant metastasis is a sign of advanced stage of ICC, which indicates a poor prognosis for a patient. Up to date, radically, surgical treatment has been considered the only effective therapy for ICC patients. Unfortunately, due to the hidden and nonspecific symptoms of ICC in the early stage, most patients present with advanced stages at the diagnosis time –7. NowadIn the present study, by using the retrospective data from the SEER database, we established two easy-to-use nomograms based on the logistic regression model for risk visualization of LM and BM in patients with ICC. By analyzing several available variables, we could predict the risk of LM and BM in patients with ICC. Being verified by C-indexes, ROC curves, and calibration curves, the novel nomograms achieved adequate accuracy and great reliability. Furthermore, the DCAs showed that the novel nomograms had good clinical application values. In addition, internal bootstrapping validation indicated the stability of two nomograms. Using the population-based data from the SEER database made the results of our study more universal than the single-center research. To the best of our knowledge, this is the first population-based study focusing on the construction of metastatic risk prediction approaches for patients with ICC. Stratifying with cutoff point of 108 for LM and 144 for BM, we could divide ICC patients in to high-risk and low-risk groups for LM and BM, respectively. Having a higher percentage of LM or BM, two high-risk groups could benefit from chemotherapy. In general, the clinical applications of our nomograms are predicting the probability of LM and BM and selecting the optimal therapeutic strategy for ICC patients.In view of our results, multivariate logistic analysis revealed that intrahepatic metastasis made the largest contribution to LM and BM in patients with ICC, followed by tumor size and gender. Specifically, the results showed that male patients had a higher risk of LM and BM, which was consistent with previous studies for other tumors , 19. It As for clinical application of the novel nomograms, two total points of each patient with ICC were obtained by several predictors. It is easy for us to screen out the patients in high risk with LM and BM. The patients can be divided into high-risk groups and low-risk groups of LM and BM according to a total point of 108 and 144, respectively, which were calculated by the maximum value of the Youden index for the ROC curves. Patients in the high-risk groups are advised to pay close attention to the presence of LM or BM. If the probability is high, patients should be suggested to conduct more valid medical check such as high-resolution CT or PET-CT. It is important to be alert to recurrence with distant metastasis during follow-up for high-risk patients, even if metastasis is not detected during first consultation. In addition, undergoing chemotherapy might be a more appropriate treatment strategy for patients in high-risk groups. Thus, these nomograms can be used for predicting the risk of LM and BM in patients with ICC and finding out patients who need to undergo chemotherapy.Nevertheless, there are also several limitations of the current study that should be considered. First of all, as a retrospective study, a selection bias was unavoidable. Second, the SEER database lacks the information about the specific site metastasis of the adrenal gland, kidney, and other organs, and brain metastasis data are relatively small. Thus, this study only predicted the lung and bone metastases of ICC patients. Third, the tumor biomarkers such as antigen 19, 9  may be associated with metastasis of ICC. However, we did not analyze it due to the unavailability of this information in the SEER database. In addition, the metastasis status in this study is at the time of diagnosis. Also, if we were able to identify the time of metastasis after surgery, Cox regression models could be established to predict the time when the postoperative metastases will occur, which might be better to predict the postoperative metastasis status. We will try to conduct this task in future researches. Finally, although it showed relatively good discrimination in the novel nomograms, as well as we performed bootstrapping during internal testing, further external validation at a large-scale multicenter cohort should be performed to test the applicability of the models.In summary, despite the limitations of the current study, this is the first time to construct nomograms for predicting the risk of LM and BM in patients with ICC. These nomograms are convenient to use and have satisfactory accuracy. Specifically, larger tumor size, male, N1 stage, higher histological grade, and intrahepatic metastasis were considered as risk factors of LM in patients with ICC, while larger tumor size, male, and intrahepatic metastasis were considered as risk factors of BM in patients with ICC. By estimating the individual risk of lung and bone metastases, clinicians can conduct individualized prediction of LM and BM in patients with ICC and give more favorable treatment recommendations, such as undergoing chemotherapy.


Independent risk factors significantly associated with development of DP were bottle-only feeding (adjusted odds ratio (aOR) = 4.65; 95% CI: 2.70–8.00), little tummy time when awake , delay of motor development , and obesity at diagnosis . Among these risk factors, delay of motor development  and obesity at diagnosis  were particularly related to severe DP. In conclusion, this study confirms that DP risk is positively associated with bottle-only feeding, infrequent tummy time, and delayed development of motor milestones. Notably, this study demonstrates infant obesity as a new risk factor for DP. Our findings suggest that obesity should be identified early and managed comprehensively in infants with DP.The prevalence of deformational plagiocephaly (DP) has increased since the recommendation of positioning infants to their back during sleeping and is affected by various biological and environmental factors. This study aimed to investigate associations between DP and perinatal or infant characteristics, including obesity. This case–control study included 135 infants  aged 2–12 months who were diagnosed with DP using calculated cranial vault asymmetric index and cranial index and 135 age- and sex-matched controls. Motor development was evaluated using the Alberta Infant Motor Scale, and obesity was defined by body mass index. Univariate and multivariate logistic regression models were used to assess potential risk factors for DP and its severity. One hundred thirty-five infants with DP were divided into the following three subgroups according to severity indicated by the cranial vault asymmetry index: mild to moderate group ( Deformational plagiocephaly (DP) is an asymmetry of the skull caused by external pressure on an infant's head in the absence of premature craniosynostosis –3. The pDeformational plagiocephaly develops in infants aged 6–8 weeks, whose heads grow rapidly while lying down, and this is analogous to how a pumpkin flattens as it grows on the ground  . Later, The prevalence of DP increases dramatically in the first 2 months after birth and is affected by various biological and environmental factors –20. PropThis study was approved by the CHA Gangnam Medical Center Institutional Review Board (GCI 2020-05-010). Informed consent was not required for this study because it is practically impossible to obtain consent during the retrospective study. Request for waiver of informed consent was approved by the ethics committee due to the retrospective nature of the study. Participants included 135 infants with DP and 135 age- and sex-matched controls enrolled between June 1, 2016 and May 30, 2020 from the CHA Gangnam Medical Center. Inclusion in the study was based on the following criteria: (1) infants were between 2 and 12 months old at the time of diagnosis of DP, (2) cranial index (CI) and cranial vault asymmetry index (CVAI) were assessed using a three-dimensional digital scanner or caliper measurements, and (3) neuroimaging results were negative for craniosynostosis. Any infants with insufficient clinical data, congenital muscular torticollis, congenital anomalies such as craniofacial or chromosomal anomalies, or any birth injury were excluded. Age- and sex-matched controls were randomly selected from the national health screening system for infants and children, and they were confirmed to have no cranial deformation on physical examination.In this study, all cases were diagnosed with positional, deformational, or non-synostotic plagiocephaly by a health care provider (E-HK), and each case was assigned a cranial vault asymmetry (CVA) value and a CI value to diagnose head deformation and assess its severity. The CVA, which defines the degree of asymmetry, is the difference in the cranial diagonals between the two sides. The CVAI is computed by dividing the total CVA by the shorter diagonal distance and then multiplying by 100 to be reported as a percentage . The CI,2) was calculated using weight and height, and BMI z-score and percentile were calculated using sex-specific values according to the 2006 WHO Child Growth Standards with WHO Anthro 2009 Software .Categorical data are presented as values and percentages, and continuous data as mean and SD. Perinatal and infant factors were analyzed in all infants with DP compared with controls. Infants in each subgroup (mild to moderate DP or severe DP) were compared with controls, and infants with severe DP were compared with those with mild to moderate DP, first by univariate model and then by multivariate model. Univariable analysis was performed to assess risk factors for all DP, mild to moderate DP, and severe DP, and the associations between potential risk factors and each group were shown by odds ratio (OR) and 95% CI. Multivariable logistic regression analysis was performed to minimize the confounding effects by adjusting for potential confounders identified in the univariate analysis and to identify independent risk factors for all, mild to moderate, and severe DP cases. Group differences of continuous variables were assessed using paired In total, 135 infants with DP participated in this study , and the mean age at diagnosis was 5.3 ± 1.8 months. Of the 135 infants, 56 (41.5%) had only plagiocephaly, and 79 (58.5%) had a combination of plagiocephaly and brachycephaly. The posterior flat side was on the right in 90 infants (66.7%) and on the left in 45 infants (33.3%). Positional torticollis was identified in 26 infants (19.3%).n = 87, 64.4%) and severe group .One hundred thirty-five infants with DP were divided into the following two subgroups according to the severity indicated by the CVAI: mild to moderate group (p < 0.001), have little tummy time when awake (p < 0.001), be obese at the time of diagnosis (BMI > 97th percentile) (p = 0.007), and present with delayed motor development (p = 0.044). However, previously proposed risk factors such as history of prematurity, large for gestational age, macrocephaly at birth, maternal history of vaginal delivery, multiple births, primiparity, and macrocephaly at the time of diagnosis were not significantly different between infants with DP and controls. Moreover, we found no difference between infants with DP and controls in mean values of gestational age, singleton birth weight, maternal age, and BMI at diagnosis.Perinatal and infant characteristics of cases and controls are summarized in Multivariate analysis found that DP was independently associated with only bottle feeding (adjusted odds ratio (aOR) = 4.65; 95% CI: 2.70–8.00) and little tummy time when awake . In addition, a 2-fold increase in DP risk was observed in individuals with delayed motor development  and obesity at diagnosis  .p < 0.001), have little tummy time when awake (p = 0.002), and be obese at the time of diagnosis (p = 0.021), and those with severe DP were more likely to have only bottle feeding (p < 0.001), have little tummy time when awake (p = 0.006), be obese at diagnosis (p = 0.004), and have a delay in motor development (p = 0.012)  . In the = 0.012) . The comIn this study, we found that only bottle feeding, little tummy time when awake, delay of motor development, and obesity (BMI > 97th percentile) at diagnosis were significantly associated with increased risk of DP. Among these risk factors, delay of motor development and obesity at diagnosis were particularly related to severe DP. Only bottle feeding, little tummy time, and delay of motor development have been identified as risk factors in previous studies, and this study is the first to identify infant obesity (defined by a BMI) as an additional risk factor for DP. This study confirms that infant care relates to DP and its severity; specifically, our findings suggest that infant obesity should be managed together with adjustments in feeding method/position, inclusion of tummy time, and attention to motor development status.Many studies have demonstrated that unvarying positioning highly contributes to the development of positional preference and positional cranial deformation , 18, 23.To date, few studies have examined the association between DP and infants' body weight at diagnosis. This study is the first to evaluate the relationship between DP and infant obesity as defined by BMI. Because BMI during the infant period increases until about 6 months after birth and then gradually decreases, the risk of overweight and obesity increases when there is excessive lactation or limited physical activity during the first 6 months , 39. In Many studies have demonstrated that rapid or excessive weight gain during infancy is associated with increased risk of childhood or later-life obesity and cardiometabolic dysregulation , 41. TraIf DP is not detected in the early stages and left to worsen, facial asymmetry or positional torticollis may also worsen , 44, andThis case–control study has several limitations. First, given the retrospective nature of this study, it was difficult to accurately identify the causal relationship between DP and clinical variables and assess the absolute risk of them; in addition, a large number of independent variables compared with the number of objects and the small number of objects of each subgroup might have influenced the results, and the associated factors identified in this study may change depending on different parenting conditions or care habits in other countries or at different time periods , 45. SecIn conclusion, our findings confirm that DP risk is positively associated with bottle-only feeding, infrequent tummy time, and delayed development of motor milestones. In addition, this study supports the association between severe DP, a delay in motor development, and infant obesity, which may predispose infants to lower activity levels and less varied positioning. Notably, we identified infant obesity as a new factor related to DP. Our findings suggest the need to assess obesity through BMI levels and to implement preventive practices against further deterioration in infants diagnosed with DP. Further prospective and longitudinal controlled studies involving obesity measurements at multiple time points should be conducted to advance the understanding of DP and its association with infant obesity.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the CHA Gangnam Medical Center Institutional Review Board. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.E-HK and KK participated in the conception and design of the study. E-HK, KK, JJ, YS, H-SL, SY, NK, and KC performed data acquisition and interpretation. E-HK drafted and edited the article and figures, reviewed the submitted version of the article, and supervised the study. All the authors contributed to the realization of the study and its publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.