Exposure therapy (ET), which follows the Pavlovian extinction model, is regarded as the gold-standard treatment for social anxiety disorder (SAD). The prospect of virtual reality in lieu of a traditional laboratory setting for the treatment of SAD has not been rigorously explored. The aim of the review was to summarize, find gaps in the current literature, and formulate future research direction by identifying two broad research questions: the comparative efficacy between in vivo ET and virtual reality exposure therapy (VRET) and the effectiveness of the Pavlovian extinction model in treating SAD. The criteria for effectiveness were effect size, relapse prevention, attrition rate and ecological validity. A literature search on recent randomized controlled trials yielded a total of 6 original studies (N=358), excluding duplication and overlapping participants. All studies supported that VRET was as effective as in vivo ET. Behavioral therapy that follows classical conditioning principles has a high attrition and relapse rate. Comparisons were drawn between the efficacy of the Pavlovian extinction model and other existing models, including third-wave approaches. The neural markers are suggested to be included as efficacy measures in treating SAD. The gold-standard treatment for SAD requires a paradigm shift through rigorous longitudinal comparative studies. The digrinciple . VirtualCan virtual reality treat social anxiety disorder using the principles of classical conditioning? The aim of this mini-review was to summarize, find gaps in the current literature, and formulate future research direction by identifying two broad research questions as follows:in vivo ET?Is virtual reality exposure therapy (VRET) as effective as Is ET based on the Pavlovian extinction model as effective as other ET or other therapy that use different principles or procedures in treating SAD?N = 358) fitted the eligibility criteria. nC = 108) and participants in the VRET (nVRET = 121) and in vivo ET (nIVET = 129) studies in unique individuals. Overlapping participants, including follow-up studies, were excluded to avoid depicting a larger sample in a misleading way. For example, The criteria of effectiveness were effect size, relapse prevention, attrition rate and ecological validity. A broader meta-analyses search was made in the scoping review to find the answer to the first research question see . Nine meg = 0.80–1.53) compared to control groups. Furthermore, none of them shows evidence that the effectiveness of VRET is inferior to in vivo ET. To date, only one longitudinal study has been done on the comparative efficacy between VRET and in vivo ET (N = 28) that in vivo ET. The effect size that compared the self-rating scores between the two groups of participants, using the ‘fear of native evaluation’ (FNE) scale, was clinically non-significant . This finding favors VRET over in vivo ET from an ecological standpoint. Extinction trials in ET are required to be conducted in multiple contexts and settings to prevent a relapse of SAD  uses the principles of operant conditioning and attempts to shift the focus of SAD patients to holistic well-being from the feared stimulus . FurtherSeveral studies reveal that the difference between the brain activity of the prefrontal cortex of SAD and control groups at baseline is statistically significant . There iin vivo ET in treating SAD. VRET has higher ecological validity than in vivo ET. Self-guided VRET in a home setting requires rigorous future investigations on the feasibility of data-driven mechanisms through remote or automated monitoring that ensure optimal intervention and prevent burnout. The future research direction of VRET studies in treating SAD should be geared toward investigating the relationship between the cultural paradigm of the VR environment and the extent of generalization of skills from virtual to real-life environments, and the relevance of designing culturally sensitive VR software. SAD treatment strategies based on classical conditioning have high attrition and relapse rate. There is a gap in the literature estimating the efficacy of therapies based on attrition rate and relapse prevention. Future research should be geared toward comparative longitudinal, relapse-prevention studies between Pavlovian exposure therapy, cognitive therapy, and third-wave approaches, such as therapy based on operant conditioning, and include both self-rating scales and neural markers as efficacy measures in treating SAD.To conclude, recent studies provide strong evidence that VRET is as effective as NC conceived the idea, designed the review protocol, conducted the literature search and drafted the article. AK revised the article and organized the funding. All authors approved the submitted version.This work was supported by three grants  from Khalifa University Abu Dhabi, UAE.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.The reviewer MA declared a past co-authorship with the author AK to the handling editor.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Evidence-based task-strengthening strategies for hypertension (HTN) control (TASSH) are not readily available for patients living with HIV in sub-Saharan Africa where the dual burden of HTN and HIV remains high. We are conducting a cluster randomized controlled trial comparing the effectiveness of practice facilitation versus a self-directed control  in reducing blood pressure and increasing the adoption of task-strengthening strategies for HTN control within HIV clinics in Nigeria. Prior to implementing the trial, we conducted formative research to identify factors that may influence the integration of TASSH within HIV clinics in Nigeria.This mixed-methods study was conducted with purposively selected healthcare providers at 29 HIV clinics, followed by a 1-day stakeholder meeting with 19 representatives of HIV clinics. We collected quantitative practice assessment data using two instruments: (a) an adapted Service Availability and Readiness Assessment (SARA) tool to assess the capacity of the clinic to manage NCDs and (b) Implementation Climate Scale to assess the degree to which there is a strategic organizational climate supportive of the evidence-based practice implementation. The quantitative data were analyzed using descriptive statistics and measures of scale reliability. We also used the Consolidated Framework for Implementation Research (CFIR), to thematically analyze qualitative data generated and relevant to the aims of this study.Across the 29 clinics surveyed, the focus on TASSH (mean=1.77 (SD=0.59)) and educational support (mean=1.32 (SD=0.68)) subscales demonstrated the highest mean score, with good–excellent internal consistency reliability . Within the five CFIR domains explored, the major facilitators of the intervention included relative advantage of TASSH compared to current practice, compatibility with clinic organizational structures, support of patients’ needs, and intervention alignment with national guidelines. Barriers included the perceived complexity of TASSH, weak referral network and patient tracking mechanism within the clinics, and limited resources and diagnostic equipment for HTN.Optimizing healthcare workers’ implementation of evidence-based TASSH within HIV clinics requires attention to both the implementation climate and contextual factors likely to influence adoption and long-term sustainability. These findings have implications for the development of effective practice facilitation strategies to further improve the delivery and integration of TASSH within HIV clinics in Nigeria.ClinicalTrials.gov, NCT04704336The online version contains supplementary material available at 10.1186/s43058-022-00289-z. Contributions to the literatureInvestigates the facilitators and barriers to the implementation of evidence-based task-strengthening strategies for hypertension control within HIV clinics in Nigeria.Identifies strengths and opportunities to leverage within HIV clinics and some challenges to address to optimize for the implementation of task-strengthening strategies for hypertension control within HIV clinics in Nigeria.Findings will inform a practice facilitation strategy to enhance the implementation and integration of evidence-based task-strengthening strategies for hypertension control within HIV clinics in Nigeria.Hypertension (HTN) remains a key risk factor for cardiovascular diseases (CVD), particularly in sub-Saharan African countries currently undergoing the epidemiologic transition of mortality from infectious disease to noncommunicable disease (NCD) , 2. PeopOne factor that may impact the integration, implementation, adoption, and sustainability of evidence-based task-strengthening strategies for HTN control is the implementation climate . DefinedAlthough implementation climate has a robust theoretical foundation , 15, fewIn an effort to promote hypertension control among people living with HIV in Nigeria, we are planning for a cluster randomized controlled trial that compares whether practice facilitation (PF) will reduce blood pressure among PLHIV and increase the adoption and sustainability of task-strengthening strategies for hypertension control. The proposed cluster randomized controlled trial would be the first attempt at the integration of HTN management care in HIV clinics in Nigeria. Prior to implementation of TASSH in Nigeria and to maximize the opportunity for success with the integration of evidence-based task-strengthening strategies for hypertension control within HIV clinics in Nigeria, we sought to explore key stakeholders’ current perceptions of barriers and facilitators to the implementation of TASSH in HIV clinics, implementation climate, and organizational readiness for change. Findings will inform the adaptation strategies needed to tailor TASSH implementation to the local context.The study was conducted in Lagos, the largest city in Nigeria, and led by the Nigerian Institute of Medical Research (NIMR). We conducted a cross-sectional study design employing an explanatory sequential  mixed-methods approach , 17—a quQuantitative data were collected using a modified practice assessment survey to examine the practice capacity of 29 geographically distinct HIV clinics across 20 different Local Government Areas in Lagos State. The 29 clinics recruited for the study were purposively selected based on the provision of comprehensive antiretroviral therapy (ART) services at the clinic sites and patient load, including private, public/government, faith-based organizations, and primary facility level.For the qualitative aspect, we convened a stakeholder’s meeting of 19 representatives of HIV and noncommunicable disease organizations from Lagos State Ministry of Health, Lagos State Primary Health Care Development Agency, Lagos State AIDS Control Agency, and the Nigerian Institute of Medical research. Stakeholders were purposively recruited to represent individuals who were either directly involved as a participating clinician in the management of NCDs and HIV or involved directly or indirectly at a policy or strategic level.We collected quantitative practice assessment data using two instruments: (a) an adapted Service Availability and Readiness Assessment (SARA) tool , 19 to aThe SARA questionnaire is a World Health Organization standardized assessment tool to assess the capacity of health facilities to provide basic health services , 19. ThiDeveloped by Ehrhart et al. , this moWe conducted a 1-day in-person stakeholder meeting that lasted for 2 h, hosted by NIMR with the key stakeholders mentioned above. The meeting focus group discussions covered the following: participant’s understanding of the purpose of TASSH and its value in the HIV clinics, their perception of its adaptability and impact on nurses’ work, and suggestions on how they can become engaged in facilitating the adoption of TASSH within the HIV clinics. The meeting was audio-recorded.A sequential analytical strategy was applied which involved a quantitative analysis followed by a qualitative analysis. Descriptive statistics ) were used to summarize responses to the survey items using SPSS  software version 25. The implementation climate scale measures were examined for internal consistency reliability, and Cronbach alphas were calculated for each subscale. The data from the stakeholder’s meeting (in an audio-recording device) were first transcribed and then analyzed using directed content analysis, which allows for the exploration of phenomenon of interest using a theory as a guide . We usedn=28/29). Among the health facility representative surveyed, 62% (n=18/29) of the respondents were females, with a median age of 40 years (IQR 37–45 years), and had worked at the current institution for less than 10 years (n=21/29). On average, clinic providers care for 394 HIV patients per month. The number of hypertensive HIV patients seen at the facility ranged from 5 to 73 patients per month. Among the participants who attended the stakeholders meeting, 8 of the participants were health providers (noted as HP in the quotes), such as physicians and nurses, within HIV clinics, whereas 11 of them were key informants (noted as SH in the quotes) from the Ministry of Health at the local government level and/or national level.The HIV clinics that participated in the survey represented 20 local government areas in Lagos, creating variability in the organizational characteristics and context. The vast majority of the health facilities surveyed were public, government-operated clinics , the majority of the stakeholders perceived this model as a solution to make more efficient use of the existing workforce and reduce the workload of overburdened healthcare professionals.A few health providers highlighted that the rational distribution of the clinical duties among cadres will allow the more specialized healthcare workers to focus solely on clinical tasks and procedures restricted to higher-level cadres. One of the healthcare providers’ notes:key aspect in the management of hypertension is diet, physical activity, taking appropriate medication and stress management which don’t require the attention of a doctor to achieve…if this task is shifted to them, the Doctors could focus on more complex tasks that require co-morbid management. (HP 1)n=23/29) of the HIV clinic representatives surveyed reported that doctors were the sole providers of lifestyle-related information for HTN management such as prompting heart-healthy diet, low sodium intake, physical activity, and eliminating tobacco and caffeine intake.Nonetheless, 79% Several stakeholders suggested the integration of the existing community health extension workers (CHEWs) into the referral systems, as this may strengthen the compatibility of TASSH intervention within the HIV clinics.Community Health Extension Workers (CHEWs) could be useful in the tracking of patients, given their close understanding of the community and direct connections with the community members, which could help take some burden off the Nurses. They could serve as a liaison to provide a comprehensive system which starts from the home down to the health system to further strengthen the referral network for the intervention. (SH3)n=6/29) and referring  HIV patients who are hypertensive, suggesting significant gaps in the continuum of care for HTN.Within the HIV clinics, less than a quarter of the clinic representatives surveyed indicated that CHEWs and other community health officers are responsible for identifying  of health facilities surveyed reported that there were training materials, journals, and other educational resources available for evidence-based practice for hypertension management within the HIV clinics. Similarly, 52% (n=15/29) indicated that their facilities provide specific conferences, workshops, or seminars on evidence-based practices. To illustrate the importance of training, one of the stakeholders provided an example where initial training of staff to implement a new process within the clinic gave them a sense of empowerment, thereby increasing their self-efficacy to carry out the given process.Access to training opportunities and educational resources was perceived as important facilitators for promoting initial uptake and sustained use of new processes within the facilities. This is particularly important as only 52% patients are no longer dying of AIDS at the rapid rate they used to, they are living longer; thus, NCD’s such as cardiovascular diseases and hypertension are now becoming more problematic; the question now is, how can we integrate the treatment of NCD’s within an already existing HIV care. (SH12)Patient needs were a major implementation driver. The majority of the stakeholders supported the goal of the TASSH intervention because they felt that it addressed their long-standing concerns about the growing burden of NCDs among HIV patients at their facilities and how to integrate HTN care into HIV clinics, as described by a stakeholder that,Stakeholders expressed that health workers at the facilities would expect some form of non-monetary incentives that are both intrinsically and extrinsically motivating to enhance the productivity of health workers with new or additional responsibilities. Some of the suggestions to accommodate the need to incentivize the health workers included social recognition, an increase in professional status, and/or competencies backed by certification.there is a need to institutionalize the initiative of providing incentives in form of professional development, as Health workers want something to showcase as part of their achievements in their CVs [Curriculum Vitae]. (SH7)n=29/29) indicated that providers at their health facility receive neither financial incentives nor commissions to use evidence-based practices for the management of diseases.Furthermore, monetary incentives were perceived by the stakeholders as an unsustainable form of compensation for managing health worker’s productivity. All the clinic representatives surveyed (n=26/29) of respondents indicated that evidenced-based practices for hypertension treatment are important to the providers in their health facilities.Despite the potential of strain that could result from adding on a new responsibility, as highlighted by one of the stakeholders, most of the health providers articulated their belief that the benefits of implementing TASSH within the HIV clinics outweigh any disadvantages. Of the HIV clinic representatives surveyed, 90% Discussion on the perceived difficulties of implementing the TASSH intervention within HIV clinics centered on challenges with dynamic role boundaries. Many cited the potential for disagreements and conflicts over roles and role boundaries among the cadres of health workers. The issues of power and authority were commonly cited as important factors that may influence relationships and patterns of collaboration among the healthcare teams. In this regard, some of the stakeholders emphasized the need to first understand the scope of practice for the lower-cadre healthcare workers at various facility levels, identify overlapping responsibilities, and then define the roles of the healthcare workers.We need to look at how services are delivered by these health workers at the primary and secondary care level especially as most patients in HIV care go to the primary care level. (SH7)persons involved need to know their limitations particularly as Nurses and CHEW are on the same salary scale and have different entry qualifications... We need to clearly define tasks that would be reallocated and let limitations be clearly identified. (SH 5)n=17/29) of the HIV clinics surveyed reported that antihypertensive drugs were often readily available at their clinics. This generated some concerns among the stakeholders as they emphatically stated that this deficiency may stifle the implementation of the TASSH intervention within HIV clinics, as resource availability was viewed to be critical in determining the level of staffs’ readiness.Generally, it was found that primary health facilities were supported by the state ministry of health to ensure the availability of basic supplies, diagnostic equipment, and first-line drug regimens related to HIV and hypertension management, but this level of support was not uniform across the different clinics, particularly at lower-level facilities. For instance, only 59%  catering to a lot of people. (SH6)A select number of flagship clinics are well stocked with drugs and equipment compared to the others. Some buoyant LGA’s have large laboratory which serves the PHC, while at some PHCs, there may have no drugs for the treatment of Hypertension. (SH5)In relation to referral channels and communications, most of the participants emphasized the need to strengthen referral networks for HTN management in order to support the decentralization of service delivery in the context of the task-strengthening approach. This was seen to be particularly useful in the event that the health worker is faced with patient needs beyond their level of competence which may require higher-level consultation or referral. It was also noted that there were “no proper patient tracking mechanisms” (SH7) in place for intra-clinic referrals and referrals between clinics and hospitals.In the context of national policies, the national Multi-Sectoral Action Plan for the Prevention and Control of Noncommunicable Diseases (2019–2025) from the Federal Ministry of Health in Nigeria identifies task-strengthening as a priority action for NCD management at all levels of care. In addition, we found that there is an existing task-strengthening and task-sharing national policy for essential healthcare services in Nigeria published in 2014. Although these policies exist, stakeholders highlighted that the policies and guidelines are not implemented at the clinics. Additionally, a stakeholder added that the task-strengthening and task-sharing national policy lacked specific actions for minimizing the workload of health workers in the clinics.The issue we have now is that there is no policy action that says we can only have a health worker take care of 50 people max, and beyond 50 people no more. (SH12)This study aimed to examine stakeholder’s perceptions of the implementation climate and other contextual factors necessary for integrating evidence-based task-strengthening strategies for hypertension control within HIV clinics in Nigeria. Using CFIR allowed for a more robust formative assessment that led to the identification of adaptation strategies needed to tailor TASSH implementation to the local context. Understanding the implementation climate from key stakeholders has been identified as a fundamental component for intervention adoption and sustainment, as engaged stakeholders are associated with higher overall positive attitudes towards the adoption of evidence-based practices in their organizations , 29. TheIndeed, participants were of the opinion that TASSH should be given top priority with managing and controlling high blood pressure rates among people living with HIV. In addition, the provision of in-service training alongside training materials, workshops, and seminars on TASSH were considered to be important for shaping healthcare workers' implementation behavior, ultimately enhancing blood pressure outcomes for people living with HIV. On the other hand, the results of the rewards subscales demonstrated that incentives such as monetary rewards were less likely to affect the implementation of TASSH within HIV clinics. Rather, support and recognitions beyond financial rewards are more likely to grow intrinsic motivation to learn about and adopt TASSH. Taken together, findings illustrate how organizational leaders at HIV clinics can align organizational policies, procedures, and practices and provide educational support to create an implementation climate that shifts healthcare workers’ attitudes and motivations towards the effective use of TASSH in practice. The presence of committed and well-informed organizational leadership and program champions has been identified as key facilitators in other studies that can mitigate organization barriers by maintaining strategic direction and ensuring that organizational resources support intervention adoption –33.In addition to the implementation climate, the results of this study indicate that there are important contextual factors within the organizations that may facilitate or hinder the integration of TASSH within HIV clinics in Nigeria. This finding is corroborated by previous studies that emphasize the importance of the fit between the intervention model and organizational characteristics fundamental for the successful implementation of EBPs , 34. Suc. The relative advantage of TASSH particularly with reducing workloads of overburdened healthcare workers, reducing clinic wait times, and increasing access to care alongside the potential complexity of TASSH underscores how intervention characteristics may exert positive, negative, or potentially neutral influence on the implementation and integration of TASSH within HIV clinics. More research is needed to understand this relationship and to test the impact of healthcare provider-focused interventions on the implementation climate and long-term sustainment of the intervention. However, planning and engagement with key stakeholders throughout the process of integrating TASSH within HIV clinics is an important implementation strategy to promote adoption, fidelity, and sustained use [Likewise, while monetary incentives were described as least beneficial with TASSH implementation climate, some stakeholders believed extrinsic incentives such as organizational recognitions, increase in professional status, and/or competencies backed by certification not only fosters more commitment but gives healthcare workers a sense of ownership with TASSH implementationined use , 37.The current study contributes to the existing literature by examining stakeholders’ perspectives of the implementation process and generates new evidence by understanding the implementation climate for the integration of task-strengthening strategies to improve HTN control among people living with HIV. This would provide information to build our understanding of which factors matter and can be used to refine implementation strategies to promote a more wide integration of HTN control into HIV care services and contribute to the field of implementation research . FindingThe results of this study should be interpreted considering some limitations. First, our study is limited to participating organizations and their staff. As such, our findings may not be generalizable to other health organizations. Nonetheless, the organizations selected for the study are within the NIMR network, where the proposed randomized controlled trial will be conducted. Lessons learned from the proposed study could inform implementation in other locations across Nigeria and are transferable to future practice-based interventions. Second, the study excluded other stakeholders, such as the patients, non-governmental organizations, and civil societies, who may have also played an important role in the implementation of the intervention. Third, the study relied on self-reported assessments from the study participants and therefore depends on the stakeholders’ perceptions and relationships with the organizations. While the self-report by stakeholders is an optimal way to measure their perceptions of the organizational climate, they may not necessarily provide an objective evaluation of the organization’s realities or practice capacities of the health centers. Fourth, given the cross-sectional data collection approach utilized for this study, it precludes our ability to make causal statements about the organizational climate that may influence attitudes towards TASSH over time . Future Despite these limitations, there are several strengths to this study. First, this study utilized both quantitative and qualitative data to improve our understanding of the implementation climate for the integration of TASSH in HIV clinics. The qualitative data corroborated the quantitative findings and added more nuanced information on the implementation climate for TASSH integration . PreviouThis study provides important insights into barriers and facilitators for implementing evidence-based intervention task-strengthening strategies for hypertension control (TASSH) within HIV clinics in Nigeria. The findings support stakeholder engagement’s importance in fostering collaboration and examining organization readiness for intervention implementation . OrganizAdditional file 1.


Due to the growing impact of the information and communications technology (ICT) sector on electricity usage and greenhouse gas emissions, telecommunication networks require new solutions which will enable the improvement of the energy efficiency of networks. Access networks, which are responsible for the last mile of connectivity and also for one of the largest shares in network energy consumption, are viable candidates for the implementation of new protocols, models and methods which will contribute to the reduction of the energy consumption of such networks. Among the different types of access networks, hybrid fiber–wireless (FiWi) networks are a type of network that combines the capacity and reliability of optical networks with the flexibility and availability of wireless networks, and as such, FiWi networks have begun to be extensively used in modern access networks. However, due to the advent of high-bandwidth applications and Internet of Things networks, the increased energy consumption of FiWi networks has become one of the most concerning challenges required to be addressed. This paper provides a comprehensive overview of the progress in approaches for improving the energy efficiency (EE) of different types of FiWi networks, which include the radio-and-fiber (R&F) networks, the radio-over-fiber networks (RoF), the FiWi networks based on multi-access edge computing (MEC) and the software-defined network (SDN)-based FiWi networks. It also discusses future directions for improving the EE in the FiWi networks. Climate change manifested by global warming caused by large amounts of greenhouse gas (GHG) emissions presents a serious issue that affects today’s society. This issue is contributed to by increased energy demand for powering today’s Information and Communication Technology (ICT) systems. This increased energy demand for ICT systems additionally poses an economic issue due to the increasing cost and consumption of energy. Therefore, improving the energy efficiency (EE) of ICT systems has become an important consideration, since addressing this issue can contribute to the global reduction of GHG emissions and operating expenditure (OPEX) costs of service providers and network owners.Despite the ability to reduce GHG emissions in some real-life scenarios , ICT is becoming a major contributor to global energy consumption . The EE Due to the abovementioned necessity for satisfying implementation demands related to the simultaneous serving of higher numbers of users, offering larger data rates or ensuring a better quality of service, mobile network operators (MNOs) in past decades upgraded their radio access network (RAN) architectures. One of the main RAN architecture upgrades is related to the replacement of obsolete and overhauled traditional waveguide and coaxial-based BSs architecture  with thoThe introduction of such modular BS design with fiber–optic cabling between BBU and RRU provides numerous advantages which primarily include higher bandwidth, reduced transmission losses and lower sensitivity to electromagnetic interference and noise. However, one additional positive aspect of such architecture is reducing the increased energy consumption of network equipment, since RRU can exploit the concept of natural air cooling, which reduces the energy needed for cooling overall BSs composed of BBU and RRU in the same cabinet .Additionally, the introduction of optical communication between RRU and BBU in D-RAN becomes the basis for the development of the newest generation of RAN architectures, which are based on centralized wireless access networks known as Cloud-RAN (C-RAN). In the C-RAN, decupled BS RRU and BBU components are placed at different locations which can be up to tens of kilometers away . LocatioBesides implementation in mobile cellular networks, the integration of fiber optics and wireless technology in access networks through the combination of fiber and wireless technologies, also known as the fiber–wireless (FiWi) concept, presents an alternative cost-effective solution to the realization of access networks. FiWi access networks integrate the high capacity of optical fiber networks with the coverage and flexibility of wireless networks. They create a robust infrastructure for the development and deployment of current and future applications and services and they are considered to be the most promising option for the realization of next-generation access networks . By usinIn a FiWi network, both radio-over-fiber (RoF) and radio-and-fiber (R&F) technologies are utilized. Radio-over-fiber (RoF) constitutes a popular communication system design that addresses the increasing bandwidth demand and enables optical and wireless integration in modern C-RAN systems. The radio-and-fiber (R&F) network, in contrast, is an approach based on connecting distributed radio transmitters  access points (APs)) and centralized WLAN controllers with fiber–optic networks. R&F networks have the advantage of building wireless local area network (WLAN)-based FiWi networks. These advantages are reflected in the possible coverage of larger areas without the limitations related to the optical back-end size, while the RoF network has a limited reach of deployed fiber imposed by the propagation delay in fiber. Using the same infrastructure for both wired and wireless services, FiWi networks can merge the traditionally separate optical and wireless access networks, thus leading to potential cost savings .The high performance requirements of future 5G networks, including extremely low latency, uninterrupted user experience and high throughput and reliability, will necessitate the use of localized services that are within RANs located closer to mobile subscribers.The multi-access edge computing (MEC) paradigm is exploited as a solution for offering services closer to mobile subscribers. Through telecom operators, information technology (IT) and cloud computing, the MEC aims to bring cloud services to the users directly from the network edge . HoweverThe paper is further structured as follows: the overview of the FiWi access networks is presented in Merging optical fiber and wireless technologies in broadband access networks by leveraging the advantages of both technologies presents a viable solution to support the increasing bandwidth demands of future applications ,12. The The most common architecture of FiWi access networks comprises optical and wireless network domains. Ethernet passive optical networks (EPONs) or gigabit passive optical networks (GPONs) are commonly used in the optical segment of the network. In the wireless domain, a wireless point-to-point or mesh network (WMN) is operated according to the IEEE 802.11, WiMAX and LPWAN standards , and celThe allocation of resources by OLTs is usually dynamic. It involves resource planning in terms of allocating time slots for data transmission to a single ONU device using time-division multiplexing (TDM) or assigning a single wavelength using the wavelength-division multiplexing (WDM) mechanisms. Such dynamic bandwidth allocation (DBA) is a key component of the TDM–PON mechanism that prevents collisions and improves bandwidth utilization through a polling scheme based on determining the ONU bandwidth requirements . ConnectIt is also possible to combine these two solutions using time and wavelength division multiplexing (TWDM), which is characteristic of Next-Generation Passive Optical Network 2 (NG–PON2) and 100G-Ethernet Passive Optical Network (100G-EPON). The TWDM–PON uses the same physical network architecture as TDMA–PON . HoweverIn classical PON networks, ONU devices terminate at user locations, where it is possible to offer the service to end users exclusively through optical media. However, in FiWi networks, ONU devices are deployed in the characteristic locations . These cThe transmission of optical signals in FiWi access networks can be implemented by RoF and R&F technology. Generally, both RoF and R&F technologies can be deployed in FiWi access networks; however, R&F technology is a very good solution for high-range FiWi networks based on the WLAN standard . In compThe application of FiWi networks is particularly interesting in sensor networks which represent the basis for the realization of IoT concepts in the fields such as telemedicine, smart agriculture, Industry 4.0, smart cities, smart buildings, autonomous driving, etc. This will result in the rapid enlargement of machine-to-machine (M2M) communications, which are characterized by a massive connectivity of communicating nodes (sensors) and transmissions of smaller-size data. Improvements to the FiWi network that could facilitate application within the IoT concept include the use of the millimeter-wave communication band (mmWave) for the transmission at high data rates over shorter distances and the concepts of network function virtualization (NFV) and SDN, which could significantly affect the reduction of capital expenditure (CAPEX) and OPEX of the network .Although the RoF network exploits the advantages of both the optical distribution network and wireless mobile network, the main challenge in the realization of the RoF concept is ensuring appropriate MAC protocol functionality. The merging of wireless and optical network segments has an impact on RoF network functionality, which is primarily reflected in the occurrence of additional propagation delays among different network segments. This can cause the expiration of certain timeouts of wireless MAC protocols that can significantly reduce network performance . For exaOne of the possible solutions related to the elimination of the MAC coordination problem is the implementation of R&F technology . While, Although flexible and robust FiWi networks have emerged as an attractive solution for the realization of today’s modern access networks, the low utilization of the optical network elements and high overhead in packet data communication raise an issue of optimizing the EE of FiWi networks. The utilization issue is a consequence of the data traffic variations wherein, during low or no utilization periods, active elements of FiWi networks consume energy as in the periods of moderate or high utilization. Therefore, improving the EE of FiWi networks is a non-negligible challenge and an active research area .Over the years, many power-saving (PS) software techniques have been adopted to increase the EE of hybrid FiWi networks. These mechanisms differ depending on whether the PS technique is implemented in an optical or a wireless domain. Most research studies are focused on increasing the EE of these two domains separately . However, it has been shown that in terms of EE of hybrid FiWi networks, cooperation between PS mechanisms of both domains achieves better results . In thisThe most popular optical back-end technology currently used in the realization of the FiWi network is the passive optical network (PON). The PON is a cost-effective point-to-multipoint network access architecture. In the PON network, OLT is allocated in the CO and via a passive optical splitter connected with numerous ONUs which are allocated near users  21]. Du. Du21]. Reducing ONU device power consumption can be achieved primarily through different PS operation modes prescribed by the ITU-T standard  Figure . These PIn ONU dozing mode, the ONU transmitter is powered off for a considerable amount of time, while the ONU receiver maintains an active state at all times. This corresponds to even lower instantaneous power consumption of the ONU dozing mode when compared with the power consumption of the power-shedding mode . The ONUAnother PS method in PONs is the implementation of the adaptive link rate (ALR) concept. It is based on energy reduction that can be achieved by adapting different transmission rates between optical devices . In optiIn addition to the aforementioned PS modes, a newer PS scheme called watchful sleep mode (WSM) has emerged and is also included in all major PON standards ,53,54. TFurthermore, the IEEE service interoperability in the Ethernet passive optical networks (SIEPON) work group (SIEPON 1904.1) standardized two additional PS mechanisms, namely, transmitter (Tx) and transceiver (TRx) sleep modes for EPON systems . SimilarTo optimize Tx sleep interval wile satisfying QoS in TDM PON systems, the authors in ref.  proposedIn contrast to the centralized sleep mechanism introduced in the SIPEON standard, the authors in ref.  proposedIn the past, the fast/cyclic sleep mechanism of the ONU has been extensively researched to reduce energy consumption in XG-PON. However, due to the emergence of new types of network traffic with stringent demands, further improvements in sleep time interval selection are required. Hence, the paper  proposedBesides the optical domain, different PS techniques have been developed in the wireless domain of FiWi networks. Since the highest consumers of energy in the radio part of the network are wireless network (front-end) devices , different solutions have been proposed for improving the EE of the wireless segment of FiWi networks. Most of the proposed solutions are based on dynamic control of the activity state of wireless network devices in accordance with traffic variations. Besides ONTs, wireless network devices can also be, at a certain moment, in an active or in a sleep state. Whether it is transmitting or being idle in the active state, wireless network devices consume significantly more energy compared with the sleep  state . Hence, Moreover, a mechanism called an adaptive power saving mechanism (PSM) was introduced in ref. , which, To address these issues associated with initial PSM, the authors in ref.  presenteEffective management of WLAN power consumption on smartphones can have a significant impact on energy consumption. The authors in ref.  have shoAs an extension of the SAPSM approach, the authors in ref.  have proIn addition to the aforementioned PS methods in the wireless domain of the FiWi network, methods for powering the locations of wireless network devices (AP and BS) using renewable energy sources have also been proposed ,43. ThesFurthermore, the authors in ref.  proposedSince the FiWi network consists of optical and wireless domains that are realized with two different technologies with versatile PS mechanisms, cooperation between these two PS mechanisms is found to be a desirable option. It was shown in refs. ,46 that For the realization of joint EE improvement in both domains of the FiWi access network, another interactive PS method based on the wireless–optical topology reconfiguration (WOTR) technique is proposed in ref.  Table 1Table 1. Due to the issues related to the increased latency and degraded EE caused by the simultaneous use of unsynchronized PS schemes in the optical and wireless domains of the FiWi network, the authors in ref.  proposedThe authors in ref.  proposedThe study found that the use of TDMA in FiWi networks significantly improves the energy efficiency while maintaining delay performance, with the feature of increasing energy savings proportionally with traffic load. Another cooperative mechanism called the delay-controlled and energy-efficient clustered (DEC) TDMA scheme was presented for the FiWi network in ref.  Table 1Table 1. In order to achieve energy conservation and ensure satisfactory QoS, a collaborative sleep technique between optical and wireless nodes was developed in ref.  Table 1Table 1. The implementation of the FiWi networks using the RoF technology is based on exploiting optical fiber as a means for the direct transport of radio frequency (RF) signals among one or more remote access (antenna) units (RAU) and network operator central office (CO) . The CO The optical modulation of the RF signal is realized through electrical-to-optical (E/O) conversion, which is required for transmitting an RF signal over an optical–fiber link. Compared with traditional coaxial-based RAN systems, the RoF network paradigm offers several advantages. Those advantages are related to the high bandwidth of fiber links with high data rates and low signal attenuation. This allows greater transport distances and better resistance to electromagnetic noise and thereby increases the flexibility of the allocation of network devices, reduces BS size due to the BS design with RRUs and BBUs, increases installation flexibility, allowing multiple operators to share the same RoF network and improves the EE through dynamic resource allocation realized using the centralization of baseband functions at CO premises .Depending on how the RF signal is transmitted through an optical–fiber link, there are two basic RoF communication techniques known as digitized RoF (D–RoF) and analog RoF (A–RoF) . In the For example, the MFH link between the RRU and the BBU designed for the LTE advanced (LTE-A) C-RAN architecture based on a common public radio interface , the D–RoF approach has one major issue. Namely, the CPRI has shown to be bandwidth-inefficient, as it uses a constant data rate for transmitting the signals . Hence, Presumably, the D–RoF-based solutions may have been sufficient for the early stages of the 5G network, but as 5G reaches its full potential, digitized optical MFH transmission based on the conventional CPRI protocol will generally not be sufficient . Analog–As the RoF integration and mobile broadband access techniques have been developed, studies focused on improving the EE of the RoF networks have been performed. An overview of research activities related to the EE improvements of the ROF-based systems is presented in One way to optimize the RoF DAS performance is to minimize the power consumed at each remote antenna unit, while providing wireless coverage to a specific area. In ref. , the autIt was shown in ref.  that DASIn ref. , the autThe authors in ref.  conducteIn ref. , for an The usage of optical fiber instead of coaxial cabling for connecting BBU and RRU locations in the D-RAN network architecture constitutes the basis for the realization of next-generation cellular mobile networks  72]. Du. Du72]. The D-RAN concept is particularly suitable for the realization of RAN as a HetNet with the large number of distributed small cells realized as elements of DAS. Small-cell communication systems realized through DAS show potential for increasing the capacity and data rate of RANs. However, such RAN communication systems must be simple and have low power consumption. To meet these requirements, the RAN architecture is evolved from D-RAN to cloud-based RAN (C-RAN). The C-RAN architecture involves separating the BBU of traditional cell sites from remote RRUs and allocating the BBUs in a central cloud location . This alAlthough three communication standards in D-RAN systems have been developed , CPRI and Open Radio equipment Interface (ORI)) for digital–optical interface communication between RRU and BBU , the CPRThe C-RAN architecture  was intrFurthermore, in C-RAN network architecture, RRU design and functionality are much simpler, and this further contributes to the reduction of BS site power consumption and maintenance costs. Additionally, the C-RAN has an architecture suitable for the implementation of cooperative techniques such as coordinated multi-point (CoMP) processing technology. The cooperation of multiple BBUs in the large cloud BBU pool using CoMP technology enables the sharing of different system information in the cloud. This can improve the spectral and EE of the RAN and also can contribute to alleviating inter-cell interference (ICI) of the densely deployed small cells .Therefore, through the implementation of the cloud-computing paradigm, the C-RAN architecture is able to aggregate multiple BS resources into a central BBU pool in the cloud. According to ref. , with suSince energy efficiency has become one of the main concerns when designing RAN, some initial research analyses have been published with respect to improving the EE of C-RAN networks and they are summarized in One additional issue with C-RAN architecture is that all of its BBUs are always active, even when user traffic is low. This leads to the high energy consumption of the BBU pool. To address this issue, the authors in ref.  proposedTwo methods for dynamic energy conservation in H-CRANs based on switching BBUs between the sleep mode and operational mode according to the changes in data traffic variations were presented in ref.  Table 3Table 3. In the C-RAN, the BBU pool serves a large number of RRU units  and by eIn ref. , the autFurthermore, the authors in ref.  developeThe authors in ref.  proposedAdditionally, the proliferation of the NFV technique has enabled the adoption of virtual machines which execute BBU functions in a way such that multiple virtual machines can run on a single, generic server at the BBU pool . By incrTo address the unsustainable growth of energy consumption caused by the increased mobile traffic, the C-RAN architecture separates the BBU from the RRH in the BSs and consolidates the BBUs into a BBU pool to allow low-utilized BBUs to enter sleep mode during decreased network activity, thereby reducing energy consumption. However, when a BBU is in sleep mode, the RRHs connected to it must be switched to another BBU, which can impact the QoS for those RRHs. To address this issue, the authors in ref.  have proThe utilization of C-RAN has proven to be effective in improving network performance. This gain is due to the smart management of RRHs with regard to power consumption and on/off operation modes. However, conventional resource allocation techniques maximize network efficiency without taking into account the overhead of RRH switching in adjacent time intervals. Therefore, in ref. , the autThe presented analyses of related works indicate that many challenges related to improving EE in FiWI networks based on the C-RAN concept have not been addressed. It can be observed that further research activities related to the development of advanced architectures, signalizations, protocols and scheduling algorithms must be performed in order to make such FiWi networks more energy efficient.The MEC concept introduces the cloud computing processes into FiWi networks, which are closer to mobile end UDs, more specifically at the mobile network edge. By exploiting an approach based on processing part of the user traffic in the cloud servers located at the edge of the mobile network, the transmission delay in the network is reduced and central servers at the cloud are less loaded. The architecture presented in This technology and architecture are key to the evolution towards full installation of the 5G networks and especially 6G networks, since it enables the transformation of mobile networks towards a programmable platform that meets the mobile cellular network requirements for increased bandwidth, lower delay and better scalability and configurability . As one The authors in ref.  reviewedFor the computational offloading scheme that involves moving intensive computing tasks to a cloud located at the edge of the mobile network is shown to be beneficial in improving EE and reducing latency for UDs in the mobile network . Hence, Two collaborative computation offloading schemes using the CM-FiWi architecture, namely, an approximation collaborative computation offloading scheme (ACCO) and a game-theoretic collaborative computation offloading scheme (GT-CCO), were studied in ref.  Table 4Table 4. Due to limitations of mobile UDs, e.g., reduced computing resources, memory capabilities and limited battery capacity, offloading compute-intensive tasks to the MEC server or a remote cloud server emerged as a viable and promising solution for today’s computation and delay-sensitive applications . This ofDue to the removal of unnecessary data traffic from optical backbone networks, the MEC-enhanced FiWi network presents a viable choice for practical implementation in cases where resource-intensive and delay-sensitive mobile applications will be used.However, the assumption that the FiWi infrastructure offers unlimited and free resources is not realistic and, hence, the energy-efficient offloading techniques must be considered in the realization of MEC-enhanced FiWi networks. Motivated by the need to develop energy-efficient offloading mechanisms for the MEC-enhanced FiWi networks, the authors in ref.  presenteIn recent years, traditional access networks have become difficult to manage due to the constant increase in the number of users and network devices, which is followed by the increased complexity of the network structure. Compared with traditional communication networks, networks exploiting the SDN concept introduce flexible, dynamic and programmable networking concepts. The implementation of SDN results in easier network management and improved overall network performance . The SDNAccording to Due to the constant network infrastructure growth, the power consumption of access networks has become one of the main concerns for companies that own larger networks and telecom operators. The SDN-based approach has emerged as a viable and effective solution for reducing power consumption of access networks . Table 1Although PON is considered an energy-efficient fixed network access technology, due to its mass deployment worldwide, PON systems need to be even more energy efficient to meet today’s green policy requirements. Due to modern consensual requirements related to ensuring more sustainable and energy-efficient operation of access networks, PON devices need to be enhanced in order to more easily adapt to such an environment. Having this as a goal, the authors in ref.  proposedIn addition, an energy-efficient SD optical access architecture based on TWDM–PON was proposed in ref.  Table 5Table 5. In order to minimize power consumption without adding additional delay in the 5G EPONs, the authors in ref.  proposedThe authors in ref.  proposedTo achieve energy-efficient computing in a specific environment such as cloud-edge FiWi networks, it is crucial to coordinate the actions of edge servers and cloud servers in order to reduce energy consumption. Therefore, the authors in ref.  presenteWhile implementation of SDN in RAN shows potential for improving EE of the FiWi networks, much work remains to be done within the areas of algorithms, standardization, architectures and interfaces.The development of new architectures, protocols and algorithms for FiWi networks has been a hot topic in the telecommunications industry in recent years. These networks combine the high speed and reliability of fiber optic cables with the convenience and accessibility of wireless technology, providing a cost-effective solution for delivering broadband services to a wide range of customers. Research on FiWi networking involves the integration of optical fiber and wireless broadband access technologies. FiWi broadband access networks resulting from the integration of optical fiber and wireless technologies can utilize both RoF and R&F hybrid networking technologies.The carbon footprint of ICT infrastructure is gaining increasing public attention and raises concerns related to global warming. This has led to increased research into developing energy-efficient solutions and research dedicated to improving the EE of the FiWi networks is not an exception. The use of fiber optic cables, which transmit data using light signals, allows FWI networks to operate with lower power requirements than traditional copper wire or coaxial cable networks. This not only helps to reduce the energy costs of operating FWI networks, but also has environmental benefits, as it reduces the carbon footprint of telecommunications infrastructure.In addition to the energy-efficient nature of fiber optic cables, FiWi networks can also incorporate other energy-saving technologies. In previous analyses presented for the RoF, R&F, MEC and SDN-based FiWi networks, it has been shown that advanced power-management schemes can be used to dynamically completely or partially turn off components in the FiWi network to reduce the power consumption of certain components when they are not in use.While FiWi networks offer significant energy-saving potential, it is important for telecommunications companies to carefully consider the energy consumption of all aspects of FiWi networks, which includes the wireless components and the fixed network infrastructure required to support them. By adopting energy-efficient technologies and practices, service providers and telecom operators can significantly help to reduce the overall energy consumption of their FiWi networks and contribute to a more sustainable future.Energy efficiency in C-RAN has become an increasingly important topic in recent years as the demand for mobile data services has continually grown. The C-RAN architecture, in which the baseband processing is centralized and the RF processing is distributed, has been proposed as a solution for improving energy efficiency in cellular networks. One of the main benefits of C-RAN is the ability to centralize baseband processing. By centralizing the baseband processing, the power consumption of C-RAN is reduced, since the centralized baseband unit (BBU) can serve more RRUs and thus can be designed to be more energy efficient in comparison with BBUs serving individual RRUs. Centralization also allows for the sharing of resources between BSs, which further contributes to reducing RAN power consumption. Furthermore, the C-RAN enables the dynamic power management of RRUs and BBUs by allowing them to sleep when the traffic is low, and wake up when the traffic demand increases. These BBU and RRU sleeping cycles contribute to the reduction of energy consumption.Additionally, recent research studies proposed a wide range of methods for reducing energy consumption in the C-RAN. These methods include techniques for optimizing the use of resources in the BBUs, strategies for managing the sleep state of the BBUs, resource utilization algorithms for increased energy savings, approaches for associating BBUs and RRUs, power management algorithms of the RRUs and the use of NFV to execute the functions for improving the EE of BBUs using virtual machines. Therefore, C-RAN architecture has the potential to significantly improve the energy efficiency of cellular networks through centralization, fronthaul compression, dynamic power management of radio resources and the use of the SDN and NFV. However, careful planning is required to ensure that the high bandwidth requirements of the fronthaul links can be met and to avoid adding complexity to the network.In the presented analyses, it is shown that EE is an important concern in the design and operation of the FiWi networks due to the fact that the energy consumption of these networks can be a significant portion of the total OPEX of network operators. One way to improve the EE of FiWi networks is to use MEC technology. The MEC allows the deployment of computing and storage resources closer to the edge of the network and thus closer to the users. This can reduce the energy consumption of the network by reducing the amount of data that needs to be transmitted over long-distance fiber–optic links between remote cloud servers and users located at the edge of the wireless network, since more data processing can be carried out locally at the edge servers. Optical fibers are already recognized for their EE and, implemented with MEC technology, can additionally diminish unneeded data transfer in optical networks. However, energy efficiency in the MEC-based FiWi networks is still largely unexplored and it should be a highly prioritized subject of future research.In addition, energy-efficient techniques for MEC-enabled FiWi networks include power-aware resource management schemes. These schemes optimize the allocation of resources to the fiber–optic and wireless links based on the traffic demand and the available energy. This optimization can be performed in combination with collaborative computation offloading schemes, which computationally redirect demanding tasks from the central remote server in the cloud to a server located closer to the users at the edge of the network. These concepts have the potential to contribute to the full proliferation of the green communications paradigm and to significantly decrease energy consumption in the FiWi networks.One advantage of using the SDN in FiWi networks is the ability to dynamically control and optimize network resources. With the SDN concept, network administrators can use a centralized controller to manage and configure network devices, which allows the simple allocation of resources and the adjustment of network configurations as needed. Such an SDN concept can also help to improve the efficiency and performance of FiWi networks, particularly in dynamic or high-traffic-demand environments. Because network configurations can be easily adjusted using the centralized controller, it is easier to add or remove devices and services as needed. This will enable telecommunication providers to satisfy the changing needs of their customers and adaptation to new technologies and trends. Overall, the use of SDN in the FiWi networks can help to improve the efficiency, performance and flexibility of these networks, making them a more attractive option for telecommunications providers and their customers.In conclusion, FiWi networks offer a cost-effective and energy-efficient solution for delivering broadband services to a wide range of customers. By leveraging the energy-saving potential of fiber optic cables and incorporating other energy-efficient techniques and strategies, telecommunications providers can help to reduce the environmental impact of their networks and contribute to a more sustainable future. The use of energy-efficient techniques presented in this survey can significantly improve the EE of FiWi networks, thus reducing their operating costs and carbon footprints.This paper presented a comprehensive survey of recent research on approaches that contribute to energy efficiency improvements of FiWi access networks. Emphasis was given to the extensive literature review of various power-saving techniques and energy-efficient models that are dedicated to the improvement of FiWi network energy efficiency. The presented review covered energy efficiency analyses of different types of FiWi networks which include the R&F FiWi networks, the RoF FiWi networks, the MEC-based FiWi networks and the FiWi networks based on the SDN concept. For the R&F networks, energy conservation techniques and research studies related to the optical and wireless domains were presented, as well as related works that deal with the improvement of FiWi networks’ energy efficiency through the cooperation of techniques in wireless and optical domains. Furthermore, two basic RoF techniques, the D–RoF and A–RoF, were elaborated in the context of energy efficiency, and an overview of research studies in the field of improving the energy efficiency of D–RoF and A–RoF systems was given. Additionally, the C-RAN architecture was reviewed through the prism of energy consumption with the presentation of current research efforts related to the improvement of the C-RAN energy efficiency. The MEC-based FiWi networks, which introduce cloud computing at the edge of the mobile network, were further presented, and articles dedicated to the mechanisms and concepts for the optimization of the MEC FIWi network’s energy consumption were highlighted. Finally, flexible SDN FiWi networks that offer high scalability and ease of management of the FiWI networks were presented, with an emphasis on research related to energy conservation techniques implemented in such networks. The literature suggests that there are many areas in which the energy efficiency of the FiWi networks can be enhanced. Overall, the overview presented in this work showed that EE is one of the major concerns in the FiWi networks and further intensive research attempts should be carried out in the endeavor of improving the energy efficiency of the FiWi networks.


This not only causes cardiovascular disability and absenteeism from work but also imposes significant healthcare costs globally. The incidence of cardiovascular diseases has escalated exponentially over the years with the major outcome in the form of CHD, stroke, and CHF. The involvement of the RAS in various diseases has been extensively researched with significant limelight on CHD. The RAS may trigger a cascade of events that lead to atherosclerotic mayhem, which causes CHD and related aggravation by damaging the endothelial lining of blood vessels via various inflammatory and oxidative stress pathways. Although there are various diagnostic tests and treatments available in the market, there is a constant need for the development of procedures and therapeutic strategies that increase patient compliance and reduce the associated side effects. This review highlights the advances in the diagnostic and treatment domains for CHD, which would help in subjugating the side effects caused by conventional therapy.The renin–angiotensin system (RAS) plays a pivotal role in blood pressure regulation. In some cases, this steering mechanism is affected by various deleterious factors (mainly  Cardiovascular diseases (CVDs) are characterized by multifaceted abnormalities represented by the inability of the heart to pump sufficient blood to meet different biological/biochemical and oxygen needs of the body at rest or during exercise. The renin–angiotensin–aldosterone system (RAAS) plays an important role in regulating the systolic and diastolic blood pressure in the body, whereas its overactivity leads to a cascade of deleterious changes in the cardiovascular and renal system and causes endothelial dysfunction of the arterial blood vessels. Several pathological conditions such as atherosclerosis, hypertension, diabetes, severe anemia, and anti-cancer drug therapy culminate in causing cardiac dysfunction leading to coronary heart disease (CHD), chronic heart failure associated with pressure overload, volume overload or myocardial infarction (MI), and ischemic heart disease . The varCVDs continue to remain the leading cause of morbidity and mortality all over the world. A wide array of mechanisms are associated with CVDs, such as atherosclerosis, hypertension, valvular heart disease, coronary heart disease (CHD), thrombogenesis, stroke, and chronic heart failure. The treatment of CVDs imposes an excessive economic burden on the society and healthcare systems globally . The conDifferent types of CVDs and risk factors involved in the progression of CHD are depicted in Atherosclerosis and thrombosis in the coronary arteries are the most frequent causes of ischemic heart disease. Atherosclerosis involves the deposition of LDL-cholesterol, foam cells, and the infiltration of macrophages and white blood cells in the endothelium of arterial blood vessels. Atherosclerosis-induced stiffness of coronary blood vessels leads to hypoxia and reduced oxygen and nutrient supply to the myocardium. The progressive narrowing and stiffening of the coronary arteries, subsequently, provokes myocardial ischemia and the imbalance between the blood supply and energy demand to the myocardium . EpidemiThe RAAS is a blood pressure regulatory system within the cardiorenal unit, with direct action to the arterioles  and additional action to the adrenal cortex . The renin–angiotensin system (RAS), as part of the RAAS without the effect of aldosterone, plays a central regulatory mechanism, amongst others, of the extracellular volume and cardiovascular system. Apart from the normal physiological functions of the renin–angiotensin system , its ovevia direct and indirect mechanisms and on the upregulation of reactive oxygen species (ROS) and the concomitant downregulation of endothelial nitric oxide (NO)   (Husain ide (NO) . Due to ide (NO)  and gut ide (NO) , the exiA. Fibroblast growth factor 23 (FGF23)—It is a protein that aids in the metabolism of vitamin D and phosphate and sodium and calcium reabsorption from the kidney . Recent B. Trimethylamine N-oxide (TMAO)—TMAO produced by the gut microbiota in body has been directly co-related with atherosclerotic heart disease  Schiatt Stubbs . It is kC. MicroRNA (miRNA)—This small non-coding RNA regulates gene expression by identifying a defective mRNA and causing its downregulation when it is detected at the cell transcription level . Many miD. Pentraxin 3 (PTX3)—Compared to the C-reactive protein, it is an independent biomarker and is expressed early in the endothelial vasculature inflammation making it a better and reliable biomarker for CHD  Chu et . It has via the modified HDL, which together cause endothelial injury ii. The inhibition of the effect of renin on angiotensin-I production iii. The inhibition of the effective angiotensin-II production from the inactive angiotensin-I (angiotensin-converting enzyme inhibitors (ACEis), such as enalapril)iv. The inhibition of the binding of angiotensin-II to the angiotensin-II receptor (angiotensin-II receptor antagonists (ARBs), such as losartan)The inhibition of the overactivated RAS results in the lowering of the blood pressure. Today, this is the most used group of antihypertensive products. The RAS-inhibition therapy can, currently, be divided into four ways according to their mechanism of action . They arIn addition to RAS-inhibitors, neprilysin inhibitors that block both the neprilysin  and angiotensin-II breakdown are used alone or in combination with RAS-inhibitors . This type of therapy reduces the blood pressure and heart failure hospitalization .B. Dietary foods—The diet of people in everyday life is the biggest source of medicine provided the correct food type and optimum amounts are consumed. Therefore, exploring healthy options is the need of the hour and designing a nutrient rich diet is required to keep diseases at bay.B1. Pomegranate—All the components such as seeds, flowers, fruits, and leaves possess various pharmacological properties. Pomegranate juice has been shown to reduce cellular oxidation and increase paraoxonase 2 activities in the peritoneal macrophage . In the via the inhibition of LDL-cholesterol, oxLDL, and triglycerides, while increasing the HDL-cholesterol. It leads to a significant inhibition of ACE after 3 h of consumption —It is a molecule causing the free radicals to become inactivated, while the reduced form binds ROS . This isC4. Lycopene—It is suggested to prevent the formation of oxLDL at the early stages, which might help in slowing the progression of CHD  Zuorro . It is aD. Phytotherapies—The bioactive compounds from fruits, vegetables, and medicinal and aromatic plants are the main acting functional moieties that have led to extensive research to exploit their therapeutic uses for different diseases.D1. Allicin—It has been shown to decrease homocysteine levels, which is an important risk factor for CHD. It also improves the impaired endothelial function due to hyperhomocysteinemia and decreases total cholesterol and triglyceride levels, which are under tight control of the RAS  Li et a Liu et . It alsoD2. Colchicine—A rat model of atrial fibrillation revealed the action of colchicine on renin inhibition, indicating its potential use in CHD treatment . It has D3. Betalain—Betalain supplementation decreases the concentration of the total cholesterol, triglyceride, and LDL-cholesterol, which slows atherosclerotic plaque formation. As angiotensin-2 induces plaque formation at an early stage, betalain may antagonize this type of progression. It also reduces intercellular and vascular cell adhesion molecules along with interleukin 6, TNF-α, and endothelial-leukocyte adhesion molecule 1  Rahimi . Even wiD4. Resveratrol—Mice studies have shown protective effects of resveratrol by its various actions on RAS components such as the increased eNOS and AT2R/Ang 1–7/MasR axis expression and ACE2 levels with a simultaneous decrease in ACE, angiotensin-II, and AT1R. Certain inflammatory and oxidative stress parameters were suppressed . A plausThe focus of this review was to evaluate the deleterious effects of the overactive RAS on the cardiovascular system and how it influences the occurrence of CHD and chronic heart failure when underdiagnosed and left untreated. The conventional synthetic therapeutics are known to cause adverse outcomes in long-term prophylaxis leading to patient discomfort and reduced compliance. The discovery of cost-effective new therapies is driven by the need to eliminate these adverse consequences associated with current treatment options. More emphasis is being placed on naturally derived remedies, which can help prevent undesirable side effects in most cases. Such alternative treatments also relieve the medical community of a significant amount of burden, provided they are prescribed as a part of routine practice. As a result of these combined benefits, the patient compliance improves. Therefore, exploring new breakthrough therapies is mandatory to control the number of mortalities and morbidities associated with cardiovascular complications and prevent CHD to progress to fatal chronic heart failure and negate the harmful effects of the RAS. This review has tried to bridge some of the gaps associated with the unawareness of natural remedies, which have been successfully studied and can be used as alternatives to conventional therapies.The results of epidemiological, experimental, and clinical studies have unequivocally demonstrated the positive impact of physical activity, antioxidant/anti-inflammation dietary interventions , obesity and diabetes reduction, and the cessation of cigarette smoking for improving the cardiovascular health and prevention of CVDs. The prophylactic measures must be dealt with collectively because there is overwhelming evidence that the occurrence of CVDs can be reduced by approximately 80% by making lifestyle modifications. Furthermore, the preventive strategies against CVDs must be targeted at the primary health promotion level before some of the important underlying causes of CVDs seriously afflict a person or a population at large. Such cost-effective preventive approaches will help in reducing not only CVDs and employee absenteeism but also the hospital and drug costs burdening healthcare systems of both developed and developing countries.


Schwannomas  are benign, single, slow-growing encapsulated tumors that originate in the sheath of cranial or spinal nerves,Descriptions have shown that about 25% of cases occur in the head and neck;The senile schwannoma (SS) is a rare variant that was first described by Ackrman and Taylor in 1951;,Surgery is the treatment of choice; there is a high rate of vagus nerve injury during this procedure.A female, 59-year-old patient reported a 10-year history of multinodular goiter and a palpable nodule in the left supraclavicular fossa. She complained of coughing upon flexing the neck and upon percussion of the supraclavicular nodule, which was gradually worsening. Computed tomography revealed a nodule in the cervical-thoracic transition point, juxtaposed to the trachea and the left lower pole of the thyroid . Fine neThe patient was operated on 21 June 2004; the initial procedure was a total thyroidectomy and dissection with preservation of the recurrent laryngeal nerves. At this point an encapsulated tumor was found close to the lower pole of the left thyroid lobe, which extended retrosternally.The vagus nerve tumor was completely removed under continuous monitoring (NIM-2® System); laryngeal innervation was preserved. The patient was discharged on the first postoperative day with no intercurrences; direct laryngoscopy after the surgical procedure revealed normally functioning vocal folds. Three years after surgery there are no signs of recurrence or changes in phonation.Histopathology showed areas of vacuolization, increased cellularity, pleomorphism and hyalinization. Immunohistochemistry was strongly reactive for vimentin and the S-100 protein, which confirmed the diagnosis of SS.Primary tumors of the vagus nerve are uncommon. Schwannomas are infrequent and the SS variant has been described previously only once.Surgery has a high rate of vocal fold injury and paralysis, particularly in tumors located close to the jugular foramen.FujinoMevioThis is the second report of a vagus nerve SS and the first report of a case in which continuous laryngeal nerve electrophysiological monitoring was used when resecting a primary vagus nerve tumor.Schwannomas should be included in the differential diagnosis of vagus nerve tumors. Whenever possible, surgical removal of these tumors should include continuous intraoperative electrophysiological monitoring of the laryngeal nerve.


This Research Topic extends the scientific coverage of the one previously published and dedicated to follicle–stimulating hormone (FSH) and its receptor (FSHR), which raised great interest among scientists in the field. FSH is a gonadotropin used in clinical practice on the one hand for the treatment of hypogonadism, on the other for infertility. In particular, FSH is used in females during assisted reproduction to stimulate multifollicular growth and ovulation and in males to boost spermatogenesis. This increasing FSH use in clinical practice favored the development of several biosimilar molecules reaching recently the market. Biosimilars and their originators (correct word)? show different glycosylation patterns, an issue worthy of further investigation. The identity and the clinical impact of the glycan structures bound to the molecule are still unclear. Similarly, the effect of an individual’s genotype on the response to FSH treatment still remains confusing. These variables are fundamental in the personalization of pharmacological approaches in assisted reproduction, although this application is still ambiguous, challenging, and incompletely understood. Further steps forward must be taken to reach full view of the mode of FSH action and to understand the role of genetics and environment in modulating the gonadal response to this hormone.Scientists in the field contributed to the elucidation of clinical and pathophysiological implication related to FSH. A collection of six research articles and two reviews deepens the role of glycosylation in FSH function, the use of the hormone in women and men undergoing assisted reproduction with different clinical pictures, new aspects of FSH intracellular signalling in endometrial cancer cells and the impact of endocrine disruptors.Dias and Ulloa-Aguirre comprehensively reviewed the complexity of FSH glycosidic forms, differentiating recently developed and commercially available molecules used for clinical treatments of infertility in humans. There is limited knowledge in this field since most of the studies available are from engineered non-gonadal host cells expressing recombinant receptors or animal models far to be fully representative of human physiology. The authors discussed how structural differences in glycosylation are related to specific biological functions and clinical effects of these drugs, such as pharmacokinetics and pharmacodynamics, and the ovarian response to controlled stimulation protocols.Bousfield et al. extended the overview on the functionally significant glycosylation variants of FSH. The study relies on an extensive molecular characterization of the multi-antennary nature of the glycan structures linked to hypo- FSH21 and fully-glycosylated FSH24 isoforms by mass-spectrometry. Structure-function relationships impacting the binding capacity and receptor assembly into multimers were pinpointed as the most intriguing and still unexplored issues of this gonadotropin’s physiology. The comprehension of these mechanisms provides an outlook into new strategies for personalized fertility treatments.Agwuegbo et al. FSHR complexes were analyzed in transfected cell models using a modified super-resolution imaging technique (PD-PALM) upon treatment with different FSH glycoforms. The authors demonstrated how receptor-receptor assemblies would be linked to glycosylation and modulate the kinetics of cAMP production, suggesting specific targeting of FSHR as a potential and novel therapeutic approach to assisted reproduction.The modulation of FSHR oligomerization and the impact on cAMP signalling of hypo- (FSH21/18) and fully-glycosylated (FSH24) hormone variants were deepened in the research article of Mahony et al. performed an observational, retrospective analysis of data from an electronic de-identified medical records database including 39 clinics in the USA to evaluate FSH dose adjustment during ovarian stimulation for assisted reproduction. This real-world data analysis highlighted that dose adjustment is common in clinical practice in the USA. In particular, dose adjustment was more frequent in younger than older women, as well as in those with a high versus sub ovarian reserve or those with ovulation disorders and polycystic ovary syndrome. The authors described how the personalization of the FSH administration is applied in real clinical practice.FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A polymorphisms on reproduction outcomes . The authors’ contribution demonstrated the role of FSHB and FSHR gene polymorphisms on both hormonal profile and assisted reproduction outcomes in women with endometriosis treated in assisted reproduction.A cross-sectional study was performed on 213 infertile Brazilian women with endometriosis and undergoing assisted reproduction, aiming to evaluate the effects of the Krenz et al.). Common andrological features, such as anthropological, semen and hormonal parameters were included, including the FSHB c.-211G>T (rs10835638) single nucleotide polymorphism. This is the first unbiased approach identifying sub-groups of idiopathic infertile men, revealing FSHB c.-211G>T polymorphism, FSH, and bi-testicular volume as strongest markers. This study confirmed the potential role of FSHB genotyping in the diagnostic routine of patients with idiopathic infertility.A retrospective cohort study was performed to determine whether idiopathic male infertility could be sub-grouped by an unbiased clustering approach and whether underlying etiologic factors could be delineated (Roy et al. reviewed the insufficiently explored issue of the the impact of endocrine disruption on FSH-dependent reproductive functions. They provided an overview on the environmental pollutants with potentially direct modulating effects on FSHR expression, including their function and related intracellular signalling cascades. Disruptors have different modes of action, mainly grouped into agonists, antagonists or inverse agonists. Compounds indirectly impacting the action of FSH and its receptor were identified as well, providing a wide picture on the interactions between these molecules and the female reproductive system. Given the increasing involvement of environmental pollutants in human activities, the issue is particularly topical.In this article, in vitro research report from Sayers et al. The article describes a comprehensive cell signalling study, revealing how FSH induces the formation of Gαi protein/β arrestins-dependent lipid droplets in the absence of cAMP accumulation. This is a new mechanism of FSH action which could occur in specific FSHR-expressing adenoma/adenocarcinoma tumors. The data were matched with the detection of varying levels of FSHR, Gαi subtypes, and β arrestin by RNAseq data analysis of endometrial tissues, providing a novel mechanism to be exploited in personalized therapeutic approaches.A novel mechanism of FSH-mediated signalling and downstream function was described in an endometrial adenocarcinoma cell line in the original The Associate Editors sincerely thank all authors for their excellent contributions to this Research Topic of Frontiers in Endocrinology. We feel that our efforts resulted in the coverage of the most recent research trends in FSH pathophysiology and genetics, deepening less well-known aspects, such as the clinical impact of hormone glycosylation, receptor oligomerization, modes of hormone action and the impact of environmental pollutants. Most importantly, we are confident that the new aspects of FSH/FSHR functioning compiled here will inspire future research and clinical approaches to inprover human fertility and combat cancer.MS, IH, LC and DS collaborated editing manuscripts published in the Research Topic. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We have read with great interest the review by Mankowska et al. and congratulate the authors on providing an overview of the use of critical flicker fusion frequency (CFFF) in medicine and particularly in diving medicine . In theiA-receptor is known for binding sedative anaesthetics with consequent opening of the ionophore for chloride-ions, causing hyperpolarization of the cell membrane and thereby signal inhibition [A-receptor [First, the paragraph describing nitrogen narcosis mentions the penetration of nitrogen into the lipids of neurons acting to interfere with signal transmission. This is an outdated view on the cellular mechanism of narcosis. Research on anaesthetic gases suggest an effect on ligand-gated ion-channels in the postsynaptic membrane of excitable neurones . Specifihibition . Nitrogereceptor . This inreceptor .Second, an incomplete description is given of the effects of air breathing at different diving depths on CFFF. The authors describe several studies that found a reduction in CFFF in divers breathing air at 405 kPa ) either inside a hyperbaric chamber or underwater ,7. This Third, in the section about “CFFF and its connection with brainwaves,” there seems to be a semantic discrepancy between CFFF, defined as ‘critical flicker fusion frequency’ and ‘flickering light.’ The description of the influence of flickering light on the electroencephalogram (EEG) has little or nothing to do with CFFF. It therefore seems out of place in a narrative review about CFFF.