Attacks using animal pathogens can have devastating socioeconomic, public health and national security consequences. The livestock sector has some inherent vulnerabilities which put it at risk to the deliberate or accidental spread of disease. The growing concern of countries about the risks of agro-terrorism and agro-crime has led to efforts to prepare against potential attacks. One recent international effort is the launch of a joint OIE, FAO and INTERPOL project in 2019 to build resilience against agro-terrorism and agro-crime targeting animal health with the financial support of the Weapons Threat Reduction Programme of Global Affairs Canada. Given the importance of strong animal health surveillance systems for the early and effective response to agro-terrorism and agro-crime, the project will use the FAO Surveillance Evaluation Tool (SET) and its new Biothreat Detection Module to evaluate beneficiary countries’ capacities to detect criminal or terrorist animal health events. This paper presents the development of the new SET Biothreat Detection Module and how it will be used to evaluate surveillance for agro-terrorism and agro-crime animal disease threats. The module will be piloted in early 2021 and, once finalized, will be used by beneficiary countries of the joint OIE-FAO-INTERPOL project. Results from evaluations using SET and its Biothreat Detection Module are expected to provide a baseline from which countries can build targeted capacity for animal disease surveillance including early detection and investigation of potential terrorist or criminal events involving zoonotic and non-zoonotic animal pathogens. Before the United Nations Biological Weapons Convention (BWC) came into effect in 1975 , 3. TodaAlthough rare, reports exist throughout history of non-state actors using or threatening to use biological agents against animals , 3, 5, 6In terms of vulnerabilities, many factors make animals more vulnerable to bioterrorism compared to humans and crops. Firstly, current intensive farming practices can facilitate and accelerate the spread of diseases , 14, 15.In view of such risks, several authors and reports have called for the development of international and national capacities for the prevention, detection and response to agro-terrorism and agro-crime , 13, 15.The aim of the project is the sustainable increase of global resilience against animal health emergencies arising from agro-terrorism and agro-crime by improving coordination between the animal health and law enforcement sector. The project focuses on the three priority regions of the Middle East, North Africa, and South East Asia where previous work of the three organizations identified gaps in various aspects of emergency management that may make them vulnerable to emergencies resulting from agro-crime and agro-terrorism . The firLastly, through a continuous coordination and communication phase, project outputs will be shared and used to produce communications and advocacy material to encourage collaboration between veterinary and law enforcement sectors. The project will culminate with a global conference on animal health and welfare emergency management to review and share lessons learned and knowledge acquired and rally support from the international community for an all-hazards and multi-sectoral approach to emergency management .To evaluate needs and capacities of beneficiary countries, the project will use the OIE Tool for the Evaluation of the Performance of Veterinary Services (PVS) and three FAO tools, namely the Laboratory Mapping Tool (LMT), the Good Emergency Management Practices (GEMP) and the Surveillance Evaluation Tool (SET). Relevant results of past Joint External Evaluations (JEE) lead by the World Health Organization (WHO) and of recent reports regarding biological security needs, trends and priorities by the United Nations Interregional Crime and Justice Research Institute (UNICRI) will also be used when available . AdditioAlthough countries may take several actions to prevent agro-terrorism or agro-crime, emphasis should be placed on early detection to counter such occurrences . TherefoSET was developed in 2017 by FAO upon request from beneficiary countries in Africa under the Global Health Security Agenda (GHSA). The tool’s objective is to provide countries with detailed guidance and recommendations to improve their national animal disease surveillance systems. SET was adapted from the OASIS tool , developed by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) , and hasSET is an Excel-based tool with 90 indicators divided into seven areas and 19 categories specific to animal disease surveillance . This is done during the first week of a 12-day mission in the target country. Stakeholders vary among countries but generally include the veterinary service’s epidemiology unit, field veterinary officers, veterinary laboratories, VPPs and CAHWS, multi-sectoral partners , the private sector, border inspection posts, slaughterhouses, markets and more. These stakeholders are identified in close collaboration with veterinary services focal points during the preparatory phase of the mission, which usually begins 1 month before the mission itself. It is also during the preparatory phase that the evaluation teams, which include SET experts and focal points from national veterinary services, are formed.During the second week of the mission, evaluators score all 90 indicators, analyze the graphical outputs, and conduct an in-depth analysis of the strengths, weaknesses, opportunities and threats (SWOT) of the country’s animal disease surveillance system. The SWOT analysis results are then used to guide the development of recommendations that are specific, measurable, achievable, locally relevant and have realistic timelines. At the end of the mission, the results and recommendations are presented to decision-makers for feedback and a report is drafted. The report, which includes a detailed action plan to improve the country’s animal disease surveillance system, is usually finalized around 60 days after the mission and posted online once cleared by the country’s Chief Veterinary Officer (CVO)  Fig. 2)2).Fig. Given the importance of strong surveillance systems in the preparedness and response to agro-terrorism and agro-crime, the OIE-FAO-INTERPOL consortium decided to use SET to obtain a detailed understanding of the beneficiary countries’ animal disease surveillance systems. However, the surveillance of potential deliberate animal disease outbreaks, particularly the investigation of these events, require additional coordination and activities beyond that of routine surveillance, such as forensic investigation, forensic sampling and testing, proper chain-of-custody processing, among others . TherefoThe Module was developed by animal health and law enforcement experts from FAO, OIE and INTERPOL with a background in epidemiological surveillance, animal health emergencies, veterinary diagnostics and biothreat reduction. An initial draft was developed between March and May 2020 based on an extensive literature review of more than 50 documents including international and national strategies and guidelines, workshop reports, peer-reviewed articles, legislation, international conventions and more. The draft was then reviewed by 14 biothreat reduction experts with different technical and geographic backgrounds Table  between The module includes 32 indicators divided into 7 categories related to the surveillance of potential deliberate animal disease outbreaks, including their investigation Table . SimilarOnce all 32 indicators are scored, the module will automatically generate a spider graph of the country’s strengths and weaknesses in the detection of biological threats (Fig. The 7 categories of the SET Biothreat Detection Module are Institutional Organization, Laboratory, Surveillance, Risk Assessment, Workforce, Data Management and Evaluation. The following sections describe the requirements for effective surveillance of suspected deliberate animal disease outbreaks and how national capacities to implement these activities are evaluated under each category of the SET Biothreat Detection Module.The timely exchange of information between animal health and law enforcement agencies is critical to contain the spread of disease and apprehend the perpetrators in a deliberate outbreak. However, several factors may delay the exchange of information including hesitancy to share information due to its sensitivity, legal barriers, and lack of awareness and guidance on how to collaborate. Lack of clear guidance on: leadership for response activities when a terrorist or criminal event targeting animals is suspected or confirmed, the role and responsibilities of each entity involved, the appropriate communication lines to be followed as well as outreach to the public may cause an overlap of efforts, waste of resources, and delayed detection of the outbreak source and of identification of the perpetrators leading to an overall inefficient response , 29, 30.Thus, the institutional organization category of the SET Biothreat Detection Module evaluates the factors that would create an enabling environment for intersectoral collaboration and efficient detection of potential deliberate animal disease outbreaks. This includes the existence of committees to discuss, develop and review strategies and plans related to agro-terrorism and agro-crime surveillance based on national needs and threats. It also includes the existence of a formal framework that outlines the organization and operation of surveillance activities for the detection of potential deliberate animal health events, the existence of focal points and mechanisms for national and international inter-sectoral collaboration particularly between animal health and law enforcement agencies, and the existence of sufficient resources.Initially, veterinary services and law enforcement have the common aim of identifying the causative agent and source of a potentially deliberate outbreak using similar methods. However, the end goal of law enforcement is to determine who committed the criminal offence and bring them to prosecution. To this end, law enforcement agencies use biological and other conventional evidence to build a case for attribution to a specific source and identify perpetrators, partners in crime and victims. Exploitation of criminal evidence may require forensic methods that delve deeper into the characterization of the pathogen and specific processing methods. These methods must be standardized, validated and meet standards for its results to be accepted as evidence in court . Yet, noMoreover, for laboratory results to be accepted as evidence in court, laboratories and field agents must comply with specific chain of custody procedures . These pThe existence of national mechanisms to meet epidemiologic and forensic laboratory needs during a potentially deliberate animal disease outbreak and the availability of guidelines on proper sample collection, transport, handling and preservation for diagnostic and criminal investigation purposes are evaluated in the laboratory category of the SET Biothreat Detection Module. The module also addresses the availability of sufficient resources in relevant laboratories and the percentage of laboratories with information systems. These information systems are important for evidence tracing, chain of custody maintenance and for timely sharing of laboratory results . FinallyAny animal disease surveillance system relies on farmers, private veterinarians, VPP, laboratories, CAHWs and other data sources to report disease events. The additional challenge for the detection of deliberate animal health events is that many classic bioterrorism or agro-terrorism pathogens are rare, non-endemic or eradicated. Therefore, the detection should also rely on the capacity of animal health professionals to recognize eradicated or exotic diseases of high risk for agro-terrorism or agro-crime , 15, 30.Early response to deliberate outbreaks also requires law enforcement and animal health authorities to share information and collaborate. Sharing of information even before confirming suspicions of a deliberate outbreak can be crucial in the identification of the source, control of the spread of disease and apprehension of the perpetrator. However, information sharing and collaboration between sectors for all outbreaks would be overly burdensome and unnecessary , 29, 30.The module also verifies the existence of guidelines or protocols for information sharing between law enforcement and veterinary services. This is important to allow for the safe exchange of information and to overcome potential barriers to the exchange such as legal restrictions . MoreoveMoreover, disease surveillance at entry points of a country, such as airports, ports, border posts, bus stations and postal services, are crucial for preventing the accidental or deliberate entry of diseases in a country . TherefoOnce a suspected deliberate animal disease outbreak is considered a credible threat, it is usually advisable to conduct a joint epidemiologic and criminal investigation between animal health and law enforcement authorities , 30, 32.In this category, the module verifies whether the country regularly conducts joint risk assessments for potential agro-terrorism and agro-crime threats involving all relevant stakeholders. The module also verifies whether all the minimum components of a risk assessment are done, and if the results are used in risk management to inform strategies, plans, lists of pathogens and toxins of concern and other relevant documents in the detection of agro-terrorism and agro-crime. These assessments are important in prioritizing efforts in the detection of agro-terrorism and agro-crime .One of the factors affecting the surveillance of agro-terrorism and agro-crime is the availability of staff with the necessary training and expertise , 32. In The loss, theft or misuse of information could jeopardize criminal investigations and place the country at risk. Ill-intended actors could use the information for several nefarious ends , 30, 32.In general, simulation exercises are done to test, evaluate, and refine plans and protocols. Joint simulation exercises and trainings between animal health, law enforcement and other relevant entities on important surveillance and joint investigation plans and protocols also build relationships between the sectors and allow staff to gain familiarity and expertise with the principles and methods of the detection of deliberate animal disease outbreaks , 30, 32.Recent epidemics, especially the current COVID-19 pandemic, show us how their impacts may span far beyond the physical health of people and animals by also affecting livelihoods, economies and food security. The UN Secretary General’s remarks to the Security Council on the COVID-19 pandemic notes that the pandemic also poses serious threats to public security and peace by eroding trust in public institutions, creating stressors that can lead to conflicts in fragile societies, postponing democratic elections or referenda, creating uncertainties that may escalate violence, hindering international, regional and national conflict resolution efforts, and by creating a potential window of opportunity for terrorists while the attention of governments is focused on the pandemic . Yet, deThe SET Biothreat Detection Module was initially developed to evaluate national agro-terrorism and agro-crime surveillance capacities and needs to inform subsequent capacity development efforts in beneficiary countries under the joint FAO, OIE and INTERPOL “Building resilience against agro-crime and agro-terrorism” project. Once piloted and finalized, the module could also be used with SET by other interested countries to obtain a baseline of country capacity for animal disease surveillance including early detection and investigation of potential terrorist or criminal events involving zoonotic and non-zoonotic animal diseases. FAO is currently planning the organization of trainings on the use of SET and its Biothreat Detection Module precisely to expand the network of evaluators throughout the world that may lead national missions.The end result of SET missions is an action plan with detailed short, medium and long-term recommendations to improve national animal disease surveillance systems. The SET Biothreat Detection Module will have the same final output to guide governments on how to improve the early detection of potential agro-terrorism and agro-crime events. Moreover, evaluations using SET and its new Biothreat Detection Module can be repeated every 3–5 years or upon request from countries to show progress following implementation of recommendations. The expectation is that such evaluations will thus support ongoing and future efforts to build resilience against agro-terrorism and agro-crime worldwide.


Monitoring physical activity in medical and clinical rehabilitation, in sports environments or as a wellness indicator is helpful to measure, analyze and evaluate physiological parameters involving the correct subject’s movements. Thanks to integrated circuit (IC) technologies, wearable sensors and portable devices have expanded rapidly in monitoring physical activities in sports and tele-rehabilitation. Therefore, sensors and signal acquisition devices became essential in the tele-rehabilitation path to obtain accurate and reliable information by analyzing the acquired physiological signals. In this context, this paper provides a state-of-the-art review of the recent advances in electroencephalogram (EEG), electrocardiogram (ECG) and electromyogram (EMG) signal monitoring systems and sensors that are relevant to the field of tele-rehabilitation and health monitoring. Mostly, we focused our contribution in EMG signals to highlight its importance in rehabilitation context applications. This review focuses on analyzing the implementation of sensors and biomedical applications both in literature than in commerce. Moreover, a final review discussion about the analyzed solutions is also reported at the end of this paper to highlight the advantages of physiological monitoring systems in rehabilitation and individuate future advancements in this direction. The main contributions of this paper are (i) the presentation of interesting works in the biomedical area, mainly focusing on sensors and systems for physical rehabilitation and health monitoring between 2016 and up-to-date, and (ii) the indication of the main types of commercial sensors currently being used for biomedical applications. Biomedical wearable sensors allow the measurement of physiologic parameters in a continuous, real-time and non-invasive way, including a wide range of advances in electrocardiogram (ECG), electromyogram (EMG) and electroencephalogram (EEG)-based sensing platforms ,2,3. TheMany healthcare devices for rehabilitation provide biosignals, such as blood pressure, blood glucose levels, EEGs, ECGs and EMGs . The maiThis section summarizes fundamental concepts needed to consider this review.In the last decade, the new advanced devices and the increasing of computer science technologies have improved telemedicine applications . A most Neurological rehabilitation medicine and its clinical research demonstrate that the damaged limb motor function can be restored to some extent through an efficient rehabilitation process. During this process, physicians must acquire and monitor the physical condition and physiological parameters to evaluate the training effect and, eventually, correct the follow-up rehabilitation training program. Information on muscle activation supports the physician in the clinical evaluation furnishing a reference for impairment and functional alterations. The ability of EMG signal in the measurement of this muscle activation makes this electrodiagnostic medicine technique very useful and relevant in neurorehabilitation, especially in the last four decades ,44. The The applications of surface EMG signals in neurorehabilitation regard: (i) the monitoring of neuromuscular pathologies, (ii) the prevention of work-related disorders and occupational therapy and (iii) the monitoring of neuromuscular changes and progress in severe patients. Information concerning the muscle activation during a movement or effort help physicians to evaluate and provide a clinical overview of both impairment and functional alteration. Another current common development of device in neurorehabilitation is represented by the acquisition of both EMG and EEG signals through biosignal amplifiers aiming to use physiological data to enhance their functionality in Brain Computer Interface (BCI) application. For example, the patient’s upcoming movements could be predicted by using electroencephalography (EEG) or electromyography (EMG). Always in BCI applications, EEG and EMG can be combined to either predict as many movements as possible or to enhance the reliability of movement prediction .Stroke represents one of the major causes of chronic motor disability among adults worldwide . In addiSurface EMG can evaluate the status of skeletal muscles, assisting in muscular training and rehabilitation. Surface EMG is becoming a popular research tool in sport and rehabilitation sciences. In athletes’ rehabilitation, EMG is useful to analyze muscle dysfunction, to detect not-correct muscle activation patterns and to assist in establishing and assessing treatment outcomes ,58,59. TThe main bioelectrical signals are generated by the heart, the brain and the muscles, producing ECGs, EEGs and EMGs, respectively. The acquisition, analysis and interpretation of these signals are fully reported in literature ,26,27,28EMG is an electrodiagnostic medicine technique to evaluate and record the muscular electrical signal generated by skeletal muscle activities . The EMGThe EMG signal is a complex and non-stationary physiological signal characterized by a low amplitude and low frequency values. Therefore, its acquisition is not easy to perform due to noise. The noise includes three main components: (i) the noise of the electronic acquisition equipment, (ii) the noise generated by skin-electrode contact and (iii) the noise added by the power frequency interference. Therefore, a well-specified acquisition and analysis system must be designed to improve the quality of EMG signal acquisition and its spatial and temporal resolution. Generally, an EMG acquisition system is composed of: (i) electrode, (ii) preprocessing stage (pre-amplifier and filtering), (iii) processing stage (amplifier), (iv) analog to digital conversion, (v) power supply and (vi) wireless transmission module , as showAccuracy: this characteristic is related to the implementation of the differential amplifier, ADC and several other components connected to inherent noise; the aim is to optimize each used component to minimize noise, ensuring accuracy;Sensitivity: this features on the ADC resolution and consequently the overall resolution of the system; it allows the physicians to understand the limits of their reading;CMRR: this is the Common-Mode Rejection Ratio, and it expresses the ability of the differential amplifier to reject common-mode signals; it plays a crucial role in avoiding 50–60 Hz power line interference;Input impedance: the optimization of this value is relevant in differential amplifier selections and implementations related to different user skin types and electrode interfaces;Input range: this specification regards hardware implementation and ADC, specifying the range of the biosignal that can be picked up without saturating the amplifier. A larger input range is preferred to acquire the entire signal, but this requires an expansion of signal resolution;SNR: this is the Signal-to-Noise Ratio, and it is the ratio between the signal’s amplitude and the background noise.Synthetically, the amplifier magnifies the difference in voltage between the inputs, attenuating the unwanted noise, aided by analog filters; then, the amplified signal is measured using an analog-to-digital converter (ADC), and this digitized signal allows further computerized analysis. Moreover, the signal acquisition can be performed into two different modalities: the monopolar acquisition performs the difference between a signal detected on the electrode concerning a remote reference placed in an electrically inactive area; the bipolar acquisition, instead, performs the difference between the signal detected on the electrode concerning another electrically active electrode. Finally, the wireless transmission module aims to connect the system with an external PC for EMG data analysis and processing as well as display, control, storage and query functions. This module is also the key element to achieve a portable performance of rehabilitation training. As reported above, EMG signal is affected by the environment, physiological and equipment noise components, so the acquired EMG signal contains a lot of information, useful and not. Therefore, a pre-processing module is necessary to remove baseline drift and power frequency by using a filtering stage composed of a low-pass filter and a high-pass filter . The denThis review has been conducted following the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) item . This reFor scientific papers, the chosen databases were PubMed, MDPI, Springer, ACM Digital Library and Science Direct, as reported in RQ1: what are the most recent contributions in literature?RQ2: what are the commonly used medical devices?RQ3: how do these contributions and medical devices support physiological monitoring in rehabilitation?RQ4: what are the future directions and opportunities for EMG signal acquisition and analysis in a rehabiliation context?The main research questions (RQ) of this study are:Biosignals, Acquisition device, Wearable device, Monitoring, Rehabilitation and Telemedicine, a total of 856 were identified as interesting for the topic of this review from 2004 to the present. From these resulting articles, 743 were removed because they did not fully satisfy the requirements of this review. Starting from these 113 remain papers, 15 contributions were also excluded because they did not report explicit considerations about EMG signals. Finally, from 98 studies, 20 contributions about wearable monitoring systems were chosen among papers published in the literature in the last 5 years to be analyzed in depth. A flow diagram illustrating our review methodology process is shown in Based on these research questions, while reviewing the existing research on keywords Rehabilitation consists of an iterative process involving assessments and specialized training, which unfortunately are often limited by healthcare centres’ restricted resources. To overcome this limitation, wearable technology should be an important, potential and valid solution to objectively assess and monitor patients inside and/or outside clinical environments. The information extracted by the use of this technology should provide a more detailed evaluation of the impairment, also allowing the identification of rehabilitation therapies . The advElectrical biosignals are important indicators of the health and fitness condition of the human body. The acquisition and analysis of biosignals such as ECG, EMG and EEG through real-time e-health monitoring systems allow the extraction of relevant and useful information to achieve better healthcare in terms of observation, diagnosis and treatment . A generEEG, ECG and EMG signals are extracted by electrodes placed on the patient and acquired by sensor devices able to process these signals and transmit them on accurate instrumentation for monitoring.Generally, these systems present heavy drawbacks regarding the limitation in acquiring and sending data at high rates, the low energy efficiency and the restricted portability due to their large size and weight. To overcome these limitations and make these systems more efficient, wearable devices are becoming essential in daily and clinical practice to allow continuous monitoring of human activity in terms of changes in biological signals. The increasing trends of wearable devices and the multimodal acquisition of different biosignals are crucial for advancing disease-diagnosis and treatment. Wearable devices perform activity monitoring through two main processes: (i) data acquisition and preprocessing; (ii) transmission, analysis and classification of acquired data. Signal preprocessing, for example, includes amplification and filtering stage; signal analysis, instead, involves averaging or extraction of relevant features to be used as training data for classifier .In literature, many contributions are available concerning the design and the implementation of wearable sensors aiming to define platforms of multimodal acquisition and recognition of different biosignals, such as electroencephalography, electromyography and electrocardiography, for continuous and automatic monitoring of human health status, improving diagnosis, follow-up and therapeutic strategies of several disorders. Wearable devices usually involve smart sensors to detect and monitor a set of physiological parameters aiming to support their continuous monitoring for diagnostic, therapeutic and control purposes . The greZhao et al.  propose Liu et al. in  propose 2 with 63.8-dB signal-to-noise-and-distortion ratio and 3.02 noise efficiency factor.Park et al.  report aAn analog front-end AFE with two-channel acquisition is described in . It is cIn , a multiA most recent contribution is given by Tran et al. in . The autA modular and wearable system for the acquisition and wireless transmission of biological signals is proposed in . This syAnother contribution is proposed in  by SarkeMazzetta et al.  propose The system presented in  consistsKim et al.  present Authors in  proposesBiagetti et al.  present Another contribution proposed by Biagetti et al. , followiXian Li and Ye Sun  present In , the aut2 area and power consumption of 0.382 mW.The authors of  propose Lee et al.  present Flexible architecture of a multi-purpose physiological signal  recorder is presented in , support2.A noise-power-area optimized biosensing front-end application specified integrated circuit (ASIC) for wireless body sensor nodes, and implantable medical devices are presented in . The ASIA summary of these contributions about wearable monitoring systems chosen among the papers in the literature published in the last 5 years is made in Wearable portable systems aim to daily acquire and processes different health data, providing early detection of pathological signs and improving the treatment and the continuous monitoring of disease. Many commercial EMG and ECG sensors are available, and they are designed and created to satisfy different specifications. In this section, the review proposes a description of the common commercial biosignal acquisition systems for physiological monitoring. These systems have been chosen to be the most used devices in health practice presenting similar characteristics to be compared.Biometrics Ltd offers different data acquisition systems to collect analog and digital data from various sensors and are available in wireless, portable and laboratory configurations. Wireless systems furnish total freedom of movement without being constrained by wires . They arShimmer offers a set of individual sensors for different parameters measurement . ShimmerBioSemi instrumentation proposes ActiveTwo biopotential measurement systems for research applications . This syFreeEMG is an electromyography device with wireless probes for the dynamic analysis of muscle activity. It is a 4G technology device for surface EMG analysis characterized by signal accuracy, absence of wires, lightness and reduced size of the probes. FreeEMG is largely used for orthopedic and neurological disorders; pharmacological treatments; the evolution of motor deficits; rehabilitation and follow-up; and athletic task optimization. PLUX develops innovative biosignal acquisition and monitoring platforms integrating wearable body sensors such as EMG and ECG combined with wireless connectivity and software applications . Two of BITalino (r)evolution kit is an all-in-one board with all the blocks pre-connected and ready to work out-of-the-box . This moBiosignalsplux represents an advanced wireless toolkit to collect and analyze reliable and high-definition biosignal data . It offeDelsys proposes complete wireless EMG-based solutions for monitoring human movement in research, clinical and educational settings . These sThe acquisition and analysis of biopotentials  are relevant in a diagnostic and therapeutic context to monitor and identify normal and/or abnormal physical conditions. In the rehabilitation field, these biopotentials became important to support human activity monitoring. Surface EMG is a widely used technology in rehabilitation research. It furnishes quantifiable information on the myoelectric signal of a muscle. Nevertheless, there is a strong contrast between the application of sEMG in clinical practice and research findings. This contrast is due to several issues including: (i) limited time and resources due, for example, to electrodes and skin preparations, electrode placements and equipment setup; (ii) clinically inapplicable sEMG system features mainly caused by the limited spatial resolution of sEMG; and (iii) lack of training and confidence in utilization of sEMG technology. Common example of issues are technical and regard signal processing and information extraction algorithms which do not directly produce clinically relevant information. Other issues concerns the user-unfriendliness of some equipment. Finally, the cost of the devices and the timing procedure to perform a measurement and to obtain a clinically useful information have also a negative impact. In terms of sensor technology, the main characteristics of a wearable system include low-energy operations, light weight and safety requirements. In addition, a wearable device must be compact and comfortable enough to be easily used. Moreover, it must be portable and guarantee continuous monitoring of human behavior through a battery power supply and wireless connectivity, respectively. Today, many commercial sensors are available to meet these requirements, and they offer different personalized solutions regarding specific needs. These sensors are characterized by small dimensions and portable configurations, making them more useful in patient control in clinical structure and at home. The limitation of modern commercial sensors is mainly due to the high cost and the complexity of the system used by a single subject. Moreover, they are not always easy to use. One of the main problems of existing biosignal technology is the high cost of commercial devices that is higher in devices with wireless technologies, which makes it easier to install on the muscle and connect with the computer; however, this requires a more complex system configuration. Very often, these commercial sensors present complex design, mainly based on sophisticated hardware with little attention toward a comfortable sensor–patient interface. Another problem regards the fact that these sensors are designed based on bench tests, models and patient simulators, ignoring the key component and working well in the simulation phase but revealing problems under real-life conditions. To improve these limitations, research prototypes are becoming very important because the newest sensor technology must meet the needs of clinicians and patients. The new generations of sensor-driven technologies should individuate the potential clinical need, identifying the key biosignals related to a specific physiological processes and seeking the development of platforms based on novel sensing technologies. These new platforms must be able to monitor the physiological processes from useful locations using novel transduction mechanisms. The hardware also should be designed and developed around these constraints and requirements. In the future, these sensors will support home-based physiological data collection, preventive healthcare programs and also facilitate remote care and rehabilitation protocols. For this reason, the future steps will regard the development of miniaturized and economic devices which will be used on a large population.This contribution is proposed as a review of the most common physiological monitoring systems in the rehabilitation field. It focuses on the EMG signal front-end as one of the main platforms to support physicians, patients and general subjects in rehabilitation protocols. In this review, many references in the literature have been presented to highlight the importance of the acquisition, analysis and monitoring of EMG signals to muscular activity control. Moreover, different commercial available EMG sensors have also been described and compared to identify the most common features of these devices in EMG acquisition. The main characteristics are portability and wireless data transfer, aiming to ensure a practical use in rehabilitation.


Bioscience Reports enters its fifth decade of continuous multidisciplinary life science publishing, here we present a timely overview of the journal. In addition to introducing ourselves and new Associate Editors for 2021, we reflect on the challenges the new Editorial Board has faced and overcome since we took over the editorial leadership in June of 2020, and detail some key strategies on how we plan to encourage more submissions and broader readership for a better and stronger journal in the coming years.As  Bioscience Reports is published on behalf of the Biochemical Society by Portland Press and is committed to the Society ideals by publishing sound science, providing a suitable home for valid data and findings in the life sciences. We welcome reproducible, appropriately replicated and controlled experiments, with conclusions adequately supported by the presented results. We encourage submissions in all areas of the molecular life sciences, both basic and applied.The Biochemical Society is one of the U.K.’s largest single-discipline learned societies, promoting the advancement of the molecular biosciences since 1911. Bioscience Reports is committed to the Biochemical Society aims of disseminating and sharing scientific knowledge, encouraging discourse and debate amongst scientists. To fully democratise our published research, Bioscience Reports has also been committed to full open access since 2012, with all papers published under the most permissive CC BY licence. All journal profits are returned to the Biochemical Society, supporting Society grant-funding and educational charitable endeavours. Since 2020, Portland Press has offered subscribing institutions a combined transformative ‘Read & Publish’ option, facilitating institutions towards full open access publishing [Bioscience Reports covers a broad range of fields, the journal has maintained an impact factor of 2.942 (issued in 2020), with a 5-year impact factor of 3.112. We feel this puts the journal in an excellent position moving forwards, hopefully allowing us to continue to encourage quality submissions, but to also grow and expand into areas that are currently under-represented, or are becoming of increased topicality.Although The start of this decade has seen many changes in the scientific community, not least following the global COVID-19 pandemic impacting on the ability of laboratories to conduct research, travel internationally to disseminate findings, and the direct effects of SARS-CoV-2 on scientists themselves, their friends and families. This has also been reflected in research featured in the journal, with a number of studies on SARS-CoV-2 recently published , includiBioscience Reports itself has undergone significant changes in 2020, not least the retirement of our previous Editor-in-Chief Wanjin Hong. We thank Wanjin for his excellent service to the journal for over 10 years, but we take this opportunity to introduce ourselves as the incoming Editor-in-Chief (Weiping Han) and Deputy Editor-in-Chief (Christopher Cooper), with our expertise being in the molecular basis of metabolic disorders and associated complications, and biochemistry and structural molecular biology of genome stability, respectively. To assist in handling increasing numbers of submissions, 2020 also saw a significant expansion of the number of Associate Editors, with 11 recruited to the Bioscience Reports Editorial Board . This has expanded the subject areas covered by the Editorial Board, including diverse topics such as stem cells, tumour microevironment, cell signalling, ADP-ribosylation, through to chemical biology and drug development. These appointments also diversify the Editorial Board’s geographical distribution . Whilst paper mills and methods to detect them have been excellently reviewed by colleagues elsewhere [A recent significant challenge faced by the journal has been the increased prevalence of falsified or fraudulent paper submissions, particularly involving manipulated images such as stock or invented images , or dupllsewhere ,8,9, thelsewhere . We espelsewhere .PubPeer (and other sources) of published potentially fraudulent and paper mill articles in 2020, we acted rapidly to assess the severity of cases and issued Expressions of Concern to papers where it was felt the issues were both significant and unlikely to have an immediate resolution. This further alerted readers to these papers under investigation, and accordingly published corrections or retracted articles at the earliest timepoint, in accordance with our publishing policies and COPE guidelines. We believe Bioscience Reports has taken great steps towards combating such fraudulent submissions, with our other immediate responses including instigating more stringent submission requirements, including the insistence of raw Western blot data and inclusion of institutional email accounts. We continue to mandate ORCID identifiers for corresponding authors, and encourage all authors to include their ORCID ID.We (as Editor-in-Chief and Deputy Editor-in-Chief), the Editorial Board, Portland Press and the Biochemical Society firmly believe in an accurate scientific record, and ensuring the integrity of the material in the journal is of the highest priority. Hence, following a sudden increase in community-driven notifications from Elisabeth Bik, and we are continually reviewing and updating our editorial processes and policies, with additional checks performed by the Editorial Office upon submission of all articles and again prior to acceptance. Portland Press’ new Data Policy also guides authors in transparent research and data presentation procedures, alongside strengthening our editorial and peer review processes. Whilst Bioscience Reports has seen significant growth in the last 5 years, with an over seven-fold increase in submissions compared with 2016  are: protein biochemistry , basic mBioscience Reports.We feel such broad research topics potentially featuring interdisciplinary studies are of interest to our wider readership, facilitating the exposure of authors’ findings outside of their immediate research field, compared with publishing in specialist journals. This combined with our fully open access publishing model and the values of the journal outlined here, we hope will encourage authors to submit their articles to Bioscience Reports, and we look forward to a successful (and post-COVID-19) future.The journal would be nothing without the publishing team, and we thank all the staff at the Portland Press Editorial Office, particularly Niamh Lynch and Zara Manwaring, the outgoing and incoming Managing Editors, respectively. We also thank the reviewers and readers too for their support in helping to build


Diabetes mellitus (DM) has been associated with cognitive complications in the brain resulting from acute and chronic metabolic disturbances happening peripherally and centrally. Numerous studies have reported on the morphological, electrophysiological, biochemical, and cognitive changes in the brains of diabetic individuals. The detailed pathophysiological mechanisms implicated in the development of the diabetic cognitive phenotype remain unclear due to intricate molecular changes evolving over time and space. This review provides an insight into recent advances in understanding molecular events in the diabetic brain, focusing on cerebral glucose and insulin uptake, insulin action in the brain, and the role of the brain in the regulation of glucose homeostasis. Fully competent mitochondria are essential for energy metabolism and proper brain function; hence, the potential contribution of mitochondria to the DM-induced impairment of the brain is also discussed. Diabetic encephalopathies are accepted complications of DM . Area-spLikewise, the results of multivariate analyses scoring the impact of prediabetes and metabolic syndrome on cognitive performance are controversial, but metabolic syndrome or impaired fasting glucose may be a risk factor for cognitive dysfunction . DespiteIn this work, recent advances in understanding the pathophysiological mechanisms of DM-linked impairment of the brain are reviewed. The work does not attempt to be fully comprehensive; it is aimed at the most important and interesting aspects of cellular processes that can progress to brain dysfunction and cognitive decline. Glucose is an essential energy source for the brain; thus the first section deals with cerebral glucose uptake and the participation of the brain in the regulation of glucose homeostasis. In the next section, attention is given to insulin and its role in the brain. Proper mitochondrial function is an inevitable prerequisite for the physiological functioning of the neurons, hence a potential contribution of mitochondria to CNS damage under diabetes is also discussed.+-dependent uptake of glutamate from the synaptic cleft into astrocytes by increasing the rate of glucose uptake to meet the energy demands of activated Na+/K+ ATPase. The increased glycolytic flux results in the production and release of lactate from astrocytes, which is then available as a fuel for neurons [+–glucose cotransporters SGLT are also of physiological importance to cerebral glucose transport, e.g., SGLT1 in the BBB may be involved in the adjustment of glucose concentration in the brain interstitium. High expression of SGLT1 was also observed in brain areas involved in learning, memory formation, energy expenditure, feeding behavior, and regulation of glucose homeostasis [In healthy individuals, the brain glucose level rises in a linear fashion with a rising plasma glucose level . Glucose neurons . Neurons neurons . GLUT3 i neurons . Na+–glueostasis . FurtherIn DM, blood glucose fluctuations are a typical feature that might affect glucose uptake into the brain by modifying transporter expression, transport kinetics, or BBB permeability. Adequate conclusions are currently lacking, as the studies struggle with controversial results, probably due to the large heterogeneous cerebral microvascular bed. Generally, the glucose transport to the brain is regulated in the endothelial capillary wall of the BBB in response to neuronal activity and involves regulation of blood supply, adjustment of driving forces for transport, and regulation of the expression of glucose transporters. Some evidence suggests a key role for the transcription factor HIF-1α in normal glucose metabolism . EarlierReduced brain glucose uptake associated with impaired glucose tolerance and insulin resistance has also been observed in mice with brain-specific knockout of the insulin-dependent GLUT4 transporter, suggesting a role for the transporter in the homeostatic regulation of glucose .In humans, studies focusing on T1DM have observed similar glucose uptake and cerebral concentrations under normo-, hyper-, and hypoglycemic conditions, indicating that the glucose-dependent regulation of GLUTs seems to be intact . MeasureNotably, there may be regional differences in cerebral glucose uptake due to heterogeneous brain architecture and area-specific functions. Thus, further studies focusing on brain regions involved in energy homeostasis, food intake, or cognitive functions are needed to gain more insight into brain glucose uptake under diabetes and other metabolic diseases.The islet-centered view of the control of glucose homeostasis via the insulin action on insulin-sensitive tissues and the key role of the liver to govern blood glucose represent the canonical explanation of regulatory mechanisms of glucose homeostasis in the body. However, recent research brings growing evidence of more complex regulation of systemic glucose. This regulation employs a highly coordinated interplay between the brain glucoregulatory system and pancreatic islets to set normal glucose levels. This circuit system can modulate blood glucose levels by both insulin-dependent and insulin-independent mechanisms ,27.In the direct mechanism , the braNon-hypothalamic brain regions also seem to be involved in the extrahepatic control of glucose production because insulin-activated Erk1/2 signaling in the dorsal vagal complex of the hindbrain resulted in the suppression of hepatic glucose production . Brain pThese findings support the hypothesis that pancreatic islets operate with a high degree of autonomy under physiological conditions, so a brain intervention required to regulate glucose homeostasis is minimal. As pathological inputs deviate the glucose level out of normal range, the role of the brain becomes more evident, and activation of the brain’s homeostatic function ensures glucose availability as the energy source.In addition to direct insulin-dependent regulation, the brain appears to have the ability to regulate blood glucose levels independently of insulin. The idea of insulin-independent regulation of blood glucose came from observations of the antihyperglycemic action of the adipocyte hormone leptin. The hormone is able to inhibit food intake and increase energy expenditure and glucose uptake in muscle and brown adipose tissue to suppress the production of glucagon and corticosterone or inhibit hepatic glucose output . The plAn increased interest in the brain participation in glucose homeostasis regulation was boosted by observations of the unexpected glucose-lowering effects of the fibroblast growth factors FGF1, FGF19, and FGF21 in obese and diabetic animals. The ability of FGFs as hormones with autocrine, paracrine, or endocrine effects to trigger signaling in the brain depends on their local expression, the presence of their receptors, or their ability to cross the blood–brain barrier. While FGF1 and the FGF receptors are differentially expressed in several parts of the brain, no expression of FGF19 and FGF21 has been found in the brain so far . FGF19 iIn summary, evidence suggests that glucose homeostasis is governed by a neuromodulatory circuit, in which the brain, islets, and peripheral tissues work in cooperation to adjust and regulate glycemia. In order for the system to work properly, intact brain sensing of the circulating glucose must be preserved . A defecAs mentioned in the previous section, the brain insulin-dependent mechanism governs glucose homeostasis. To do this, insulin must enter the CNS and activate cellular signaling pathways. Despite a debate regarding local synthesis in the brain, brain insulin originates predominantly from the periphery, where its level fluctuates depending on physiological or pathological states. The restricted permeability of the BBB and the size of the molecule do not allow insulin to enter the CNS directly. It enters the brain mostly through receptor-mediated transcytosis after binding to insulin-binding sites of the BBB endothelial cells . The insIt is not clear whether the insulin transporter is a separate protein or a classic receptor. The receptor can exist in A and B isoforms . Both isDifferent roles of the IR isoforms appear not to be exclusive determinants of insulin/IGF actions. Evidence suggests that both the IR-A/IR-B ratio and hybrid receptors may play an important role in final effects triggered by hormone binding. The IR expression is tightly regulated at three molecular levels by mechanisms not to be fully understood yet. IR regulation takes place at the promoter level in a developmental- and tissue-specific manner  at a posEndothelial IRs are considered to be a key entry point for insulin into the brain, hence their role in insulin transport and signal cascade has been studied on several experimental levels. The initial studies in brain capillaries have brought evidence of the reduced IRs in obesity and hyperinsulinemia as well as increased endothelial binding and insulin transport through the BBB in experimental-induced DM ,67. LateFindings from endothelial cell cultures also indicate that IRs participate in insulin transcytosis, but the transport may be affected by specific factors and conditions, e.g., L-glutamate, inhibition of NO-synthase, high-fat diet, hypertriglyceridemia, or elevated plasma levels of the intestinal hormone cholecystokinin ,74,75. SBesides acting as insulin transporters, IRs can also operate as classical signal transduction receptors and affect the BBB permeability by modulating the expression/activity of transmembrane proteins involved in the formation of brain endothelial junction complexes. Increased BBB permeability has been reported in experimental diabetic animal models . InsulinFully functional astrocytic IRs are also required for appropriate insulin and glucose entry into the brain. Proper insulin signaling in astrocytes plays a key role in effective hypothalamic neuronal responses and regulation to appropriately counteract fluctuations in systemic glucose availability. Insulin action in astrocytes also regulates gliotransmission and modulates behavior .Recent research has started to reveal the complex role of IRs in the CNS, though many issues still need to be addressed. Deciphering the role of the brain IRs in detail will provide the opportunity to modulate IR activity in a personalized and disease-specific context and will open a new avenue in the treatment of diabetic encephalopathology and other CNS pathologies.2O2 and this signal preceded activation of the IRs [2O2 signal exceeded the threshold, even in the presence of high insulin concentrations. Moreover, the signal was ultra-sensitive to H2O2 scavenging, suggesting that a pathological increase in H2O2 scavenging antioxidant enzymes may also limit insulin signaling in the brain. Since IRs are concentrated at synapses that become enriched with mitochondria in the period of synaptic activity, a disturbance in the redox activation of IRs may represent another factor contributing to insulin resistance and cognitive impairment.Insulin action is inevitably linked to proper mitochondrial function, and, not surprisingly, aberrant mitochondria in the brain are connected to insulin resistance, metabolic syndrome, diabetic encephalopathies, neurodegenerative diseases, and aging. Alterations in electron transfer chain (ETC) function, energy metabolism , mitocho the IRs . Althougm), mitochondrial respiration, the enzymatic activities of the respiratory chain, and energy levels were reported in the cortex and hippocampus of diabetic rodent models [m, published experimental data appear to be less conclusive. Besides numerous variations in experimental design, this inconsistency probably reflects many pitfalls of ROS measurement, especially in clearly assigning their origin to mitochondria [Any exogenous or endogenous stresses can perturb mitochondrial function, ROS production and ultimately impact brain energy metabolism. Neurons are especially vulnerable to mitochondrial stress since the energy stress-induced diversion of the physiological metabolic program of preferential utilization of glucose for regeneration of glutathione in the pentose phosphate cycle to the glycolytic pathway can weaken the antioxidant defense of neurons ,91. The t models ,93,95, dt models , or diabt models ,98. On tt models . Considechondria .Mitochondria are an integral part of the cellular network of adaptive and defensive responses aimed at sensing and adapting to alterations in nutrient supply or at limiting oxidative damage. In the brain, the expression and distribution of uncoupling proteins (UPCs) UCP2, UCP4, and UCP5 were induced by metabolic and oxidative challenges, suggesting the relevance of mitochondrial uncoupling to the control of neuronal, neuroendocrine, and autonomic responses . Within The insulin–mitochondria interplay is apparently observable in the processes of activating the mitochondrial stress response, as described in the next section.Metabolic disturbances in DM, such as ETC dysfunction, ROS-mediated oxidative stress, or neuroinflammation invade cellular and mitochondrial proteomes. When the proteome alters its properties, damaged and misfolded proteins and unassembled precursors can accumulate and provoke proteotoxic stress. In response to mitochondrial proteotoxic stress, the cell activates an adaptive program referred to as the mitochondrial unfolded response (UPRmt). The program, as a component of the cellular stress response pathways, represents the signaling pathway where various stress stimuli, such as misfolded and accumulated proteins, mitochondrial DNA mutations, inhibition of mitochondrial chaperones and proteases, alterations in mitochondrial dynamics, or metabolic and oxidative stress, elicit a nuclear transcriptional response to reestablish cellular and mitochondrial homeostasis . Of noteThe upregulation of mitochondrial chaperones and co-chaperones, mainly the group of heat shock proteins  and proteases , constitutes the strongest cell response to stress. The Hsp response is predominantly cytoprotective because chaperones have the potential to attenuate pathology by the clearance of aggregated proteins, e.g., amyloid proteins. They also prevent further aggregation by inhibiting the nucleation and elongation processes of cross-seeding and facilitating cellular repair and defense mechanisms . In DM, Several studies have also suggested a link between mitochondrial stress and neuroinflammation via Hsp60′s interaction with Toll-like receptors, which leads to the production of proinflammatory mediators, such as TNF-α, IL-1β, IL-6, and IL-8 ,120. HypNeuroinflammatory processes, a result of mitochondrial impairment, were also noticed in the model of metabolic syndrome (MS), a precondition for obesity, DM, and cardiovascular diseases. An important feature of MS is the deficiency of silent information regulator sirtuin 3 (Sirt3), the mitochondrial member of the group of NAD+-dependent lysine deacetylases. Deacetylases control a wide range of cellular processes, among them, Sirt3 controls energy metabolism processes, antioxidant defense, and mitochondrial dynamics . The impHealthy and fully functional mitochondria are maintained by unique equilibrium among the processes of mitochondrial biogenesis, removal of damaged mitochondria by mitophagy, and mitochondrial dynamics, which are regulated by mitofusins Mfn1, Mfn2, Drp1, and OPA1. Mitochondrial dynamics in the brain are associated with feeding, glucose homeostasis, and whole-body metabolism, and disorders of mitochondrial fission–fusion proteins are observed in obesity, DM, and neuroinflammation . Mfn1 haFuel and energy homeostasis is maintained by the intricate synchronization of afferent and efferent signals from the periphery and CNS. While the canonical explanation of systemic glucose regulation is founded on the function of exocrine in the pancreas, the homeostatic role of the brain is less clear, particularly in view of insulin-independent regulation of blood glucose. Recent evidence, however, suggests that the pancreas is not a stand-alone regulator but a component of a larger regulatory system integrating other critical homeostatic regulators governed by the brain . The faiEven if intensive research is still warranted to fully understand the impact of diabetes on the brain, the decipherment of the cooperative and controlling mechanisms and molecular mediators implicated in DM-linked brain impairment and neurodegeneration will be of great use for the development of new therapeutic strategies. It is reasonable to assume that effective treatment strategies will be aimed not at one particular target but at a complex interdependent network of targets that will alleviate multiorgan damage in diabetes.


Accompanying the development of biomedicine, our knowledge of glioma, one of the most common primary intracranial carcinomas, is becoming more comprehensive. Unfortunately, patients with glioblastoma (GBM) still have a dismal prognosis and a high relapse rate, even with standard combination therapy, namely, surgical resection, postoperative radiotherapy and chemotherapy. The absence of validated biomarkers is responsible for the majority of these poor outcomes, and reliable therapeutic targets are indispensable for improving the prognosis of patients suffering from gliomas. Identification of both precise diagnostic and accurate prognostic markers and promising therapeutic targets has therefore attracted considerable attention from researchers. Encouragingly, accumulating evidence has demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis and oncogenesis of various categories of human tumors, including gliomas. Nevertheless, the underlying mechanisms by which lncRNAs regulate diverse biological behaviors of glioma cells, such as proliferation, invasion and migration, remain poorly understood. Consequently, this review builds on previous studies to further summarize the progress in the field of lncRNA regulation of gliomas over recent years and addresses the potential of lncRNAs as diagnostic and prognostic markers and therapeutic targets. Gliomas, originating from glial or precursor cells, which are categorized into astrocytomas, ependymomas and oligodendrogliomas, are the most common malignant primary tumors of the central nervous system (CNS) , 2. In aApproximately 98% of transcripts do not encode proteins in the human genome, and this category of RNA is known as noncoding RNA (ncRNA). Long noncoding RNAs (lncRNAs), accounting for approximately 80-90% of ncRNAs, are transcripts consisting of more than 200 nucleotides that typically lack protein-coding capability and were once regarded as transcriptional noise . IntriguAs mentioned above, lncRNAs are associated with both cellular physiology and disease origination and progression by regulating gene expression . Additiovia microRNA response elements (MREs) and thus perform negative regulatory functions, exerting critical post-transcriptional regulatory effects  was enhanced by LINC00689-mediated elimination of miR-338-3p, which facilitated malignant progression of glioma cells. As a consequence, the LINC00689/miR-338-3p/PKM2 axis functions as a carcinogenic driver in gliomas . Moreovegression . CorrespWNT axis . The oncWNT axis . These rBy interacting with signaling pathways, lncRNAs can facilitate tumorigenesis. For example, silencing lncRNA MIR22HG inhibited GBM aggressiveness by suppressing the Wnt/β-catenin signaling pathway , while cThe interaction between RNA-binding proteins (RBPs) and lncRNAs plays a non-negligible role in the advancement of glioma. The expression level of EZH2 positively correlated with the malignancy of glioma and promoted the malignant behavior of glioma . Chen etMedical diagnosis in the twenty-first century is gradually moving from clinical pathology to molecular pathology. With the development of bioinformatics, an increasing number of studies have identified lncRNAs as biomarkers for glioma diagnosis and prognosis by exploring RNA microarrays, and advances in microarray and high-throughput RNA-seq technologies have provided numerous valuable lncRNAs for the diagnosis and prognosis of gliomas.The detection of serum HOTAIR levels can be employed for the clinical diagnosis of glioma, as reported by Tan et al.  These reThe BTB parallels the blood-brain barrier (BBB) and is comprised of vascular endothelial cells, basement membrane, and glioma cells. This structure can seriously impede the entry of drugs into the tumor microenvironment, resulting in poor drug efficacy and extremely unfavorable patient prognosis –61. Cons6-methyl-guanine-DNA methyltransferase (MGMT), which restores the damage caused by TMZ, resulting in the resistance of glioma cells to TMZ (Temozolomide (TMZ) is an oral alkylating agent that passes through the BBB, adding methyl groups to the purines of DNA to cause DNA damage and apoptosis for therapeutic effects , 68. Cons to TMZ . A novels to TMZ . Sun ands to TMZ . In addis to TMZ . Recentls to TMZ . The tums to TMZ . The lncs to TMZ . CASC2 hs to TMZ . High exs to TMZ . LncRNA s to TMZ . LncRNAss to TMZ . In summAngiogenesis is a requirement for the growth and metastasis of gliomas, which are solid tumors. Additionally, extensive evidence has demonstrated that the formation of novel blood vessels participates in the development and metabolic processes of tumors. Therefore, vasculogenic mimicry is considered a hallmark of malignant tumor development. Hence, antiangiogenic treatment is anticipated to be an additional efficacious strategy for glioma. Chen and colleagues demonstrated that overexpression of NKILAT was negatively correlated with survival time in glioma patients, and NKILAT augmented the Warburg effect and angiogenesis in glioma, suggesting that it may be a promising therapeutic strategy . In addiIn addition, lncRNAs that exert regulatory effects by binding to RBP also have the potential to become therapeutic targets. Lin28a elevated the expression and stability of SNHG14, while deletion of SNHG14 increased the expression of IRF6, which inhibited the transcription of PKM2 and GLUT1 and thus impaired glycolysis and proliferation of glioma cells and induced apoptosis. Therefore, considering the lin28a/SNHG14/IRF6 axis as a target provides novel insight for the treatment of glioma . AdditioOver the previous decades, lncRNA studies have made major progress in the field of glioma research due to the rapid development of bioinformatics, and a series of lncRNAs have been found to act as indispensable factors in the occurrence and progression of glioma. LncRNAs act as ceRNAs in the cytoplasm to regulate glioma progression at the post-transcriptional level or to regulate gene expression through interactions with proteins in the nucleus. However, the mechanisms of most lncRNAs remain unclear. Therefore, the specific mechanisms of lncRNAs need to be further clarified. Glioma continues to be a major challenge to human health, and its advanced aggressiveness, chemoresistance and recurrence are the main factors contributing to the poor prognosis. Theoretically, there are numerous lncRNAs, such as HOTAIR, H19 and NEAT1, that can be applied as diagnostic and prognostic indicators of glioma. It is also possible that many lncRNAs can overcome TMZ resistance, modulate BTB permeability and control glioma angiogenesis, all of which are theoretically effective therapeutic strategies. Regrettably, no successful clinical use of lncRNAs has been achieved yet. In prospective research, lncRNA-centered gene regulatory networks should be constructed to elucidate the regulatory mechanisms of lncRNAs in tumor cells and then used as diagnostic, prognostic, and therapeutic indicators in clinical practice to improve the survival of glioma patients. One of the focuses of basic research is translation to the clinic to improve the survival of patients. Translating basic research into clinical strategies is a long road that will require generations of researchers to eventually understand the full picture of the function of lncRNAs in glioma at both the scientific and clinical levels.JQ and XM wrote the draft and revised it. JC and CJ designed the tables. All authors contributed to the article and approved the submitted version.This study was supported by The National Natural Science Foundation of China , Excellent Young Talents Project of Central Government Supporting Local University Reform and Development Fund (0202-300011190006), Karolinska Institutet Research Foundation Grants 2020-2021 (No. FS-2020:0007), The Heilongjiang Postdoctoral Science Foundation , and The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2019-102).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.


Macular xanthophylls, which are absorbed from the human diet, accumulate in high concentrations in the human retina, where they efficiently protect against oxidative stress that may lead to retinal damage. In addition, macular xanthophylls are uniquely spatially distributed in the retina. The zeaxanthin concentration (including the lutein metabolite meso-zeaxanthin) is ~9-fold greater than lutein concentration in the central fovea. These numbers do not correlate at all with the dietary intake of xanthophylls, for which there is a dietary zeaxanthin-to-lutein molar ratio of 1:12 to 1:5. The unique spatial distributions of macular xanthophylls—lutein, zeaxanthin, and meso-zeaxanthin—in the retina, which developed during evolution, maximize the protection of the retina provided by these xanthophylls. We will correlate the differences in the spatial distributions of macular xanthophylls with their different antioxidant activities in the retina. Can the major protective function of macular xanthophylls in the retina, namely antioxidant actions, explain their evolutionarily determined, unique spatial distributions? In this review, we will address this question. It is accepted that the yellow pigmentation of the macula lutea is a consequence of the selective accumulation of two dietary xanthophylls, namely zeaxanthin  and lutein, in the human retina . The thiThe retinal spatial distributions are different for zeaxanthin, meso-zeaxanthin, and lutein, and the meso-zeaxanthin and zeaxanthin-to-lutein ratio changes as the eccentricity moves away from the fovea ,16,17. TAll ultraviolet (UV) light below 295 nm is absorbed by the cornea, and wavelengths between 300 and 315 nm and all UVA (315–400 nm) are absorbed by the crystalline lens . WavelenFor pigments in the same organic solvent, the absorption spectrum for zeaxanthin is similar to that of lutein and only shifts by approximately 5 nm in the long-wavelength region . AdditioThe role of carotenoids as a blue light filter is not fully understood. It is not clear whether macular xanthophylls are important for the reduction of chromatic aberration and light scattering  or for the absorption of blue light before it excites potent photosensitizers present in the photoreceptor layer and retinal pigment epithelium (antioxidant performance). Many authors suggest that macular xanthophylls may be involved in the protection of the retina through many mechanisms, not just one function. The density of blue cones rises as the macular xanthophylls increase toward the center of the fovea. The reduction of light captured through blue light filtering in this region makes sense because the foveola is free of blue cones. It is well known that several carotenoids, including zeaxanthin and lutein, located in the oil droplets of birds’ eyes, work as high-energy light cut-off filters ,42. ThesMacular xanthophylls are very efficient at quenching singlet oxygen as compared with vitamin E, which is another lipid-soluble antioxidant present in the retina. It is common knowledge that a longer conjugated double bond system is associated with a greater singlet oxygen quenching rate constant in organic solvents ,49. ThusAlthough the mechanism of singlet oxygen quenching by macular xanthophylls in simple organic solvents has been extensively studied, the same physical mechanism of the singlet oxygen quenching by both macular pigments in the lipid membrane systems has been investigated less extensively. Molecular organization of macular xanthophylls in lipid membranes and xanthophyll–lipid membrane interactions are crucial for proper antioxidant functioning. Singlet oxygen quenching may be efficient only when macular xanthophylls exist in monomeric form. For large aggregates, the ability to quench the excited state of oxygen is reduced to zero. The singlet oxygen quenching rate constants for macular xanthophylls in the lipid environment have been investigated by several authors see . CantrelThe macular xanthophylls accept deactivation of already existing singlet oxygen but may also prevent the generation of this excited form of oxygen. In fact, macular xanthophylls offer triple protection to cells against single oxygen: (i) they quench singlet oxygen directly, (ii) they prevent the generation of singlet oxygen by quenching the excited triplet state of photosensitizers, and (iii) they prevent the photosensitizers from being excited  and hydroxyl radical (OH•) [Macular xanthophylls not only quench singlet oxygen but also act as scavengers of the superoxide anion radical  ,69,70,71The mechanism against the hydroxyl radical mostly occurs through formation of the adduct radical, as shown in the equation below:Trevithick et al. have used electron spin resonance–spin trapping to evaluate the scavenging ability of different carotenoids, including macular xanthophylls . They reMacular xanthophylls protect the retina from photochemical damage by preventing lipid peroxidation . The retina is vulnerable to oxidative damage due to (i) exposure to light, (ii) a high concentration of oxygen, (iii) an abundance of photosensitizers, and (iv) a high concentration of polyunsaturated fatty acids (PUFAs) ,74. The The first approach to determine the orientation of the macular xanthophyll molecule within the lipid membrane was based on the measurements of the linear dichroism of carotenoids embedded in the oriented lipid multi-bilayers . In thesThe macular xanthophyll content seems to be high in the human eye retina, but its concentration in the lipid bilayer portion of the membrane is much lower than 1 mol% . TherefoHuman retina membranes contain high amounts of polyunsaturated fatty acids such as DHA, PUFAs, and VLC-PUFAs, which, together with rhodopsin, are isolated from POS disc membranes as a DSM fraction ,94,97,98Both macular xanthophylls have poor aqueous solubility but high solubility in lipid membranes, much higher than nonpolar carotenoids. The incorporation of zeaxanthin and lutein into phospholipid liposomes (the multilamellar vesicles) was studied by Socaciu et al. . The mulAs mentioned in Numerous studies have provided evidence of a correlation between increased dietary macular xanthophyll intake and the increase in macular pigment density ,111,130.The first separation of a carotenoid from a human retina was performed by Bone et al. in 1985 . The autIt is also important to understand why zeaxanthin is located in the central part of the retina, which is the region where the risk of oxidative damage is the highest. The studies involving lipid membranes explain how the lipid bilayer affects the organization of macular xanthophylls, including orientation , localization (distribution between membrane domains), solubility (monomers versus aggregates), and even optical properties (monomers versus blue-shifted aggregates and red-shifted aggregates). The orientations of lutein and zeaxanthin molecules in the lipid bilayer are similar  . Such trOf the many carotenoid studies, only a few of them compare the antioxidant properties of zeaxanthin with those of lutein and compare their different behaviors in the human retina. Such studies may help to explain the unique accumulation of zeaxanthin in the fovea (see reference  for revi


Gliosarcoma is a rare malignant brain tumor, characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. We first report a case of temporo-mesial gliosarcoma, extended to the crural and ambient cisterns, with direct involvement of the ipsilateral third cranial nerve and encasement of anterior choroidal, posterior communicant and posterior cerebral arteries, presenting without symptoms of peripheral neuropathy. A 61-year-old woman with 1-month history of intense bilateral frontal-temporal headache resistant to pharmacological therapy and paresis of the left lower midface underwent surgical resection, through pterional trans-sylvian approach, of a right temporo-mesial gliosarcoma which directly involved the ipsilateral oculomotor nerve. Reported cases of gliomas with direct involvement of a cranial nerve, from the third to the twelfth, are very rare, whit no cases of gliosarcoma described. Because of its rarity, sometimes this entity is not considered as diagnostic hypothesis and is misdiagnosed, both during preoperative diagnostic evaluation and during the surgery. Gliosarcoma is a strong challenge for neurosurgeons and neurooncologists because of low incidence, poor prognosis and limited reported cases on literature. This case shows unique features for localization, pattern of growth and clinical presentation. Gliosarcoma, a variant of IDH-wildtype glioblastoma, is a rare malignant brain tumor , characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation A 61-year-old woman with 1-month history of intense bilateral frontal-temporal headache resistant to pharmacological therapy and paresis of the left lower midface was observed. The brain computed tomography  showed aThe neurologic examination at admission showed static signs of central paresis of the seventh cranial nerve on the left side while no deficit of the third cranial nerve involved by the lesion was evident after accurate clinical exploration.The patient underwent right pterional trans-sylvian approach. Firstly, the surgical removal was addressed to the tumoral component involving the temporal pole, which appeared as a soft, greyish-pink mass, with central necrotic yellowish area, moderately vascularized; then, once sylvian fissure was opened, the neoplastic component involving the medial part of the temporal lobe and extending to the ambiens and crural cisterns was exposed: it appeared as a firm greyish mass with a small yellowish central core. This last component was strongly adherent to the cisternal part of third cranial nerve and encompassed the anterior choroidal, the posterior communicant and the posterior cerebral arteries, thus the complete resection was not possible.Postoperative course was characterized by transient right ptosis and mydriasis, which disappeared on the POD 3, and by improvement of the central paresis signs of contralateral midface. Post-contrast brain MRI performed 48 hours after surgical procedure showed a satisfactory tumor removal, with a small residual area of contrast enhancement.The histological and immunohistochemical studies  reportedAt discharge, the patient was addressed to the oncological team for the Stupp protocol administration.No progression-disease was detected on brain MRI with contrast performed 3 months after surgery.Reported cases of gliomas with direct involvement of a cranial nerve, from the third to the twelfth, were very rare Because of the small number of cases reported in the literature due to the low incidence of GBM with direct cranial nerve involvement and no cases of gliosarcoma, sometimes this kind of lesion is not considered and is misdiagnosed, both during preoperative diagnostic evaluation and during the surgery, hypothesizing the tumor origin from the nerve with secondary extension to the near brain parenchyma, or from heterotopic neuroglial cell dissemination from leptomeningeal gliomas or gliomatosis Concerning the macroscopic features, based on sarcomatous component amount, gliosarcoma with high connective tissue percentage have the appearance of a firm, well-circumscribed mass, which can be mistaken for a metastasis or, when attached to the dura, for a meningioma, whereas lesions less rich in connective tissue may have features more similar to a glioblastoma. Concerning imaging features, gliosarcoma usually presents as a well-demarcated solid mass, often on peripheral location, with heterogeneous enhancement, moderate or marked surrounding edema and abutting dura , but witThe pattern of growth shows a rate of extracranial metastases upon 11% for gliosarcoma Glioblastoma and gliosarcoma are similar in terms of clinical behavior, treatment and prognosis Gliosarcoma is a strong challenge for neurosurgeons and neurooncologists because of its low incidence, poor prognosis and limited reported cases on literature. This case shows unique features for localization, pattern of growth and clinical presentation.Informed consent was obtained from the patient involved in this case.


In this review, we will focus on how peripheral regulatory cells implicated in innate and adaptive immune responses are involved in the physiopathology of MS. Moreover, we will discuss how these cells are thought to act and contribute to MS histopathology, also addressing their promising role as promoters of successful remyelination within the CNS. Finally, we will analyze how understanding these protective mechanisms may be crucial in the search for potential therapies for MS.Multiple sclerosis (MS) is a chronic, autoimmune, and neurodegenerative disease of the central nervous system (CNS) that affects myelin. The etiology of MS is unclear, although a variety of environmental and genetic factors are thought to increase the risk of developing the disease. Historically, T cells were considered to be the orchestrators of MS pathogenesis, but evidence has since accumulated implicating B lymphocytes and innate immune cells in the inflammation, demyelination, and axonal damage associated with MS disease progression. However, more recently the importance of the protective role of immunoregulatory cells in MS has become increasingly evident, such as that of myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) and B (Breg) cells, or CD56 Multiple sclerosis (MS) is a chronic, immune-mediated, and multifocal demyelinating disease of the central nervous system (CNS). It is one of the most common causes of neurological disability in young adults, and to date, there is still no cure for this condition . The pre+ T cells that escape negative selection and clonal deletion pass through a disrupted blood–brain barrier and enter the CNS. These activated CD4+ T cells lead to the recruitment of other inflammatory cells, such as microglia, macrophages, and B cells, which in turn drive the production of the antibodies and pro-inflammatory cytokines that destroy the myelin sheath . N. N+Ly-6GIn MS and EAE, there are several immune cells that might be among the principal pathological orchestrators of MS, where the failure to fully resolve inflammation participates in chronic inflammation. The resolution of inflammation is the result of complex interactions between peripheral and resident CNS cells. In this review, we highlight the information available regarding the role of immune regulatory cells in the maintenance of tolerance and remyelination in MS. The data regarding peripheral immune regulatory cells are controversial, but overall, these cells seem to be impaired or altered in MS patients. We also reveal the complex relationship between the regulatory cells located at the periphery and those at sites of CNS inflammation, suggesting that future studies should better analyze the regulatory cells in the CNS to shed further light on their role in MS pathogenesis. The literature offers controversial results regarding the role of regulatory immune cells in MS, probably due to the use of different protocols, the wide variety of phenotypes to define regulatory cells, and the variation in patient cohorts and treatments. In this sense, better understanding of endogenous mechanisms involved in the resolution of inflammation might lead to novel therapeutic strategies targeting regulatory cells. However, these data have been largely overlooked, and the establishment of definitive research protocols remains to be established. Currently, different therapies with immunomodulatory actions and the potential to re-establish immune homeostasis could be beneficial in MS disease. In conclusion, the immune mechanisms involved in the resolution of peripheral inflammation and in the promotion of remyelination in MS must be considered in conjunction with opening the door to future treatment strategies that effectively induce peripheral and CNS tolerance, contributing to more complete MS resolution.


This systematic review provided synthesized evidence regarding the effectiveness of the interventions promoting the human papillomavirus (HPV) vaccination in college-aged population. The HPV infection is the most prevailing sexually transmitted disease. Despite the availability and effectiveness of the 9-Valent HPV vaccine, the vaccine coverage among young adults remained low. In witness to the increasing burden of HPV-related infections and cancers, research focused on the vaccination interventions should be conducted to determine the effectiveness of the vaccination strategy and address the gap. The search was conducted through PubMed, Cochrane, and CINAL. Studies were included if they (1) included vaccination programs, (2) target population was young adults aged 17–26, (3) examined factors associated with the intervention effectiveness, (4) were published in English, and (5) were published between February 2010 and February 2020. HPV-related knowledge and intentions toward HPV vaccination were all reported increased after the intervention. Increased HPV vaccination intentions were found associated with the increased vaccine initiation and completion. Among bisexual or homosexual individuals, females were found more likely to complete the HPV dose 2 and 3. The review findings suggested using vaccination interventions incorporated with educational components to promote vaccine uptake among young adults. Supportive interventions tailored to different populations and settings are crucial to address the suboptimal HPV-related knowledge and vaccination status among the young beneficiaries. Human papillomavirus (HPV) infection has been found as the most common sexually transmitted disease and greatly linked with genital infections such as genital warts. Specific types of HPV virus are also found responsible for cervical cancers, oropharyngeal cancers, and cancers of the penis, vagina, or anus . Among wApproximately over 70 million people in the USA were found infected with HPV sometime during the late adolescence and young adulthood, and fourteen million people are newly diagnosed with the infection each year . RegardiThe available 9-valent HPV vaccine is found effective in prevention of more than 90% HPV-related cancers . The safDespite that the distribution of the 9-valent HPV vaccine started at the end of 2016, the vaccine uptake rates in the USA remained unsatisfactory and failed to meet the objectives of the Healthy People 2020 targeting for eliminating health disparities nationwide . As per In review of the previous research, systematic reviews of HPV were primarily related to the prevalence and disparities in HPV infections, the efficacy and safety of the HPV vaccines, the measurement used in vaccine acceptability, the predictors or factors regarding HPV vaccine acceptability, and the role of health care providers in improving the vaccination initiation. The evidence they had compiled provided some insights into vaccination interventions aiming at improving the vaccination coverage, but the comprehensive review combining the factors which contribute to HPV vaccination, with vaccination intervention development and vaccine uptake evaluations, is scarce , 17, 18.The aims of this study are to investigate the effectiveness of HPV vaccination interventions in college aged adults, critically evaluate and synthesize the intervention approach to improve vaccine coverage, also add insights into the feasibility and acceptability of the intervention, and further inform the practice and policy of the HPV vaccination among young adults. This present review embodies new emerging evidence and incorporates possible prerequisites for making informed decisions regarding HPV vaccination interventions at both the individual and community level. Countries out of the USA which achieved promising results of HPV vaccination campaigns were also included in the review to provide more insights across nations.This author searched the PubMed, Cochrane, and online version of Cumulative Index to Nursing & Allied Health Literature (CINAL) independently to identify peer-reviewed studies published between February 2010 and February 2020. The search was limited to English language and with keywords and relevant Medical Subject Headings (MeSH) subject terms, including HPV, human papillomavirus, vaccine or vaccination, immunization, uptake, intervention, and students. Finally, references from systematic reviews and references from the studies identified were also assessed for inclusion in the review process.Studies were eligible for inclusion if the following criteria were fulfilled: interventions were developed to increase HPV-related knowledge and vaccination rate and provided quantitative data for HPV vaccination coverage specifically. Interventional, observational, and systematic studies were all eligible. Studies that only provided qualitative results, only published as abstracts and protocols, or only assessed HPV knowledge, awareness, attitudes, intentions, and barriers to vaccination were excluded. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed during the search, both article titles and abstracts were scrutinized first, and then relevant full-text articles were obtained and reviewed by this author to further confirm that verification criteria were met.This author extracted information about intervention and assessed risk of bias. The risk of bias and the certainty in evidence were evaluated for each study by using the Cochrane Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This approach results in three level of risk of bias and four levels of quality of evidence. Critical factors for determining the grade for each study are listed in detail for the approach, including the risk of bias, evidence quality rating scale, and descriptions of the ratings.Seventy-eight references had been screened, and a total of 10 relevant articles met the selection criteria for this review. One (10.0%) of the studies was a cross-sectional analysis . Three (n = 9) focused on college students, and one study included both employed women and undergraduate students for comparison. Three studies were conducted outside of the USA, including one in China and two in Canada. Sample size of participants in the studies ranged from 200 to 1703. Four studies recruited both male and female participants, with six studies focused on females only (see Table The study participants’ ages ranged from 18 to 38 years old. The majority of the studies (All the interventions targeted for boosting the human papillomavirus (HPV) vaccine acceptability and coverage among young adults. Among the ten interventions reviewed, five studies described the use of theory-based interventions, and key factors of the Health Belief Model (HBM), the Transtheoretical Model (TTM), and the Information, Motivation, Behavioral skills model (IMB) were reported to be applied to improve design of the interventions , 20, 23.α = .75~.95) [A range of pre- to post-intervention survey questionnaires and human papillomavirus (HPV) vaccine initiation and completion rates were used to evaluate the effectiveness of the interventions. Reasons stated for being unvaccinated were explored as well. The follow-up evaluations were conducted 3 months up to 1 year to measure the HPV vaccine dose initiation and completion. Instruments used in the studies examined the topics covering HPV-related and HPV vaccine knowledge and awareness, HPV and HPV vaccine beliefs and decision-making factors, self-efficacy, and vaccine uptake. Most of the studies used self-reported measurements, and two studies 20%) reviewed medical records for vaccine uptake assessment % reviewe. One stu.75~.95) , 19, 21..75~.95) .n = 7) did not address adequately follow-up, and nine studies had flawed measurement of outcomes due to the limited evidence of the instrument validity. Two studies were found to be of low risk of bias, four of medium risk, and four of high risk. Seven of the ten studies included in the review were graded as moderate level of quality of evidence, as a result of the majority of randomized controlled studies(n = 4) not specifying allocation concealment and blinding procedures, one study being observational and flawed design and measurements as potential threats to construct, internal, and external validity. Two randomized controlled studies discussed randomization procedures, one described the use of allocation concealment mechanism with sequentially numbered, opaque sealed envelopes, and another described that the investigators and research nurses in the field were blinded to the allocation sequence [All the studies lacked in-depth description of participant attritions, most of the studies -related infections, HPV vaccination intentions, and the vaccine uptake rates among college students aged 17–26. Constructs of the interventions and evaluations of the outcomes were also identified.In the review, all studies included vaccination interventions or programs that promoted the vaccination intentions and behaviors among college-aged students. Most of the studies assessed HPV-related knowledge, including the knowledge of cervical cancer, individuals’ perception of the risk of the disease, attitudes or intentions toward vaccination, and perceived barriers to the vaccination. The study participants’ intentions of receipt of the vaccine were found positively linked with improved awareness and knowledge of HPV-associated infections. These results imply that emphasizing the educational components in the development of vaccination intervention would improve the effectiveness of the intervention.A significant increase in the HPV-related knowledge, attitudes, and acceptability of the HPV vaccine were found in the study participants upon completion of the interventions , 19–22. Additionally, perceived severity of HPV infection, susceptibility to the HPV infection, and benefits of the vaccine were identified among the factors that positively affected the participants’ intentions to get vaccinated , 16. AddTwo major types of interventions emerged in the review, those with the theory-based approaches and those without. Promising health care outcomes were identified in both types in terms of the increased level of knowledge about the HPV infections and HPV vaccine. Increase in the HPV knowledge was found in the immediate post-intervention surveys while with one exceptional study identified significant improvement in HPV knowledge 3 months following the intervention –23. The The vaccination interventions identified in the review were also varied in settings and modalities to deliver. Most of the interventions had been completed in a one-time-only session, and reinforcement afterwards was provided in the form of reminding messages for the vaccine appointment or providing additional educational information –22. The This review only included peer-reviewed articles to facilitate the inclusion of relatively good quality work. During the review, a systematic approach was followed based on PRISMA checklist, and critical appraisal of each article was conducted following the guidance of the GRADE approach. The overall quality of the included studies was moderate, and campus-based convenience sampling, insufficient description of participant attritions and allocation concealment and blinding procedures in trial studies, self-reporting measures, and limited evidence of the instrument reliability and validity were found as the major factors that could possibly increase the risk of bias in the studies and jeopardize the transferability and generalizability of the study results. Several areas were prompted for future studies, which primarily centered on long-term assessments of the intervention effectiveness; development and evaluations of tailored vaccination interventions to manage the gender disparity, socioeconomic disparity, diversity in sexual orientation, and different ethnic groups; the difference in parental, peer, and interprofessional roles; and impact in health prevention regarding HPV-related infections and cancers. Moreover, in the light of generally low level of knowledge of HPV prevention and better immune response with the younger population, effective strategies addressing comprehensive and quality sexual health education at younger ages should be examined.On the whole, this review indicated the complex of contributing factors to a successful HPV vaccination intervention. The approaches adopted in the studies achieved higher level of HPV-related knowledge, vaccination intentions, and higher vaccination rates in comparison of the pre-intervention status. Insights and gaps identified in the review could possibly be applied to guide sexual health education and inform the policy of the HPV vaccination and other vaccine preventable diseases, especially for the vaccinations that are not included in the national program. More robust study designs for studying the associations between HPV vaccination interventions and vaccine uptake rates across different settings and populations are also underlined in the findings of the review.