Low back pain has been found as a major cause of global disease burden and disability. Intervertebral disc degeneration is recognized as the vital factor causing low back pain. Intervertebral disc degeneration has a complex mechanism and cannot be avoided. Traditional strategies for the treatment of intervertebral disc degeneration cannot meet the needs of intervertebral disc regeneration, so novel treatment methods are urgently required. Exosomes refer to extracellular vesicles that can be released by most cells, and play major roles in intercellular material transport and information transmission. MicroRNAs have been identified as essential components in exosomes, which can be selectively ingested by exosomes and delivered to receptor cells for the regulation of the physiological activities and functions of receptor cells. Existing studies have progressively focused on the role of exosomes and exosomal microRNAs in the treatment of intervertebral disc degeneration. The focus on this paper is placed on the changes of microenvironment during intervertebral disc degeneration and the biogenesis and mechanism of action of exosomes and exosomal microRNAs. The research results and deficiencies of exosomes and exosomal microRNAs in the regulation of apoptosis, extracellular matrix homeostasis, inflammatory response, oxidative stress, and angiogenesis in intervertebral disc degeneration are primarily investigated. The aim of this paper is to identify the latest research results, potential applications and challenges of this emerging treatment strategy. The entire spine of the human body has been damaged from birth by exercise or other causes. Over time, the damage has evolved into low back pain. Almost everyone has a short history of acute low back pain in their lifetime. However, some people will develop chronic low back pain and suffer from pain continuously . Low bacTraditional treatment strategies include surgical and non-surgical treatments, capable of achieving limited intervention in the IVD microenvironment through nerve root decompression, removal of degenerated IVD, pharmacological or non-pharmacological therapy, or interventional therapy. However, traditional treatment strategies focusing on mitigating symptoms do not facilitate the regeneration of IVD at a cellular level, and they even accelerate the degeneration of adjacent stages . AccordiIVD, the largest avascular tissue in the human body, is composed of fibrocartilaginous tissue that can be divided into three distinct parts, including a highly hydrated gelatinous nucleus pulposus (NP) located at the center, annulus fibrosis (AF) composed of collagen fiber lamellas around NP, as well as cartilaginous endplate (CEP) with hyaline cartilage structure that connects the vertebral bodies. The above complex structure takes on a critical significance to transmit and absorb the mechanical load between vertebral bodies and maintain flexibility .NP is largely occupied by notochordal cells (NCs) at the early stage of growth and development. Subsequently, chondrocyte-like cells exhibiting poor water retention capacity tend to replace resident NCs. The above age-related transition can result in a reduction in IVD’s hydration status and more stronger and less compliant functional spinal unit overall . The extAF falls into internal and external parts, which include 15–25 layers of highly packed inclined collagen fiber lamellas and interspersed proteoglycans . The lamSimilar to other parts of IVD, the main components of CEP consist of water, type II collagen and proteoglycans, which are characterized by structural semipermeable barrier and load-bearing functions . From thIVDD occurs consistently with age. When NCs in NP are progressively lost in early life, catabolic processes begin to be dominant . The delAt first, NCs stimulate the proliferation of NPCs and synthesize proteoglycans, especially due to the secretion of connective tissue growth factor (CTGF). When NCs are gradually lost, and the dialogue with NPS cells ends, IVDD occurs . At the As a response to tissue damage, inflammation involves a vascular response as well as activation and recruitment of immune cells, however, with IVD being an avascular tissue, it is not surprising that the inflammatory response is different in this case . DegradaTraditional surgical procedures including resection and transforaminal lumbar interbody fusion of degenerative IVDs or restricted interventions with conservative therapies are now invariably linked to loss of function, unsatisfactory outcomes, or the accelerated emergence of secondary complications . Therefovia in vivo viral or non-viral vectors, and these cells with a controlled genetic makeup will produce proteins that support IVD regeneration and have greater long-term efficacy than injected growth factors , which basically fall into three categories, including apoptotic bodies, ectosomes, and exosomes. Exosomes are different from others since they originate from the endosomal pathway involved in endocytic recycling or lysosomal degradation. This is a strictly and uniquely regulated intracellular process in which composition and function may be already determined when they are secreted into the extracellular space . The aboNo matter how the biogenesis of exosomes proceeds, they are composed of phospholipid bilayer structures that encapsulate lipids, proteins, and nucleic acids . Lipids,After being expelled, exosomes enter body fluids from the extracellular space and circulate at least for a short time; they eventually reach recipient cells locally or remotely . The intIn 2007, valadi et al. first systematically described RNAs in exosomes . SimilarNot only are intracellular miRNAs vital regulators of gene expression, the transfer of miRNAs through exosomes also plays an essential role in IVDD. Accordingly, over the past few years, exosomes and exosomal miRNAs have become the research focus in IVDD treatment. The existing research results have been summarized and classified in accordance with the different focus mechanisms of various studies, and the focus is placed on the regulatory roles of exosomes and exosomal miRNAs in apoptosis, senescence, and proliferation of IVD, as well as metabolic homeostasis, oxidative stress, inflammation, and angiogenesis of ECM .in vitro model, treatment with exosomes derived from mesenchymal stem cells (MSCs) significantly enhanced the viability and proliferation of degenerative IVD cells obtained from patients with degenerative IVD and chronic low back pain, and inhibited their apoptosis , which are potential options for treating IDD . Excessive senescence prevents cell cycle transition and stops proliferation, reduces cell viability and deteriorates the microenvironment, which is causally related to the occurrence of IVDD . ExosomaMetabolic disturbance of the ECM is the most striking feature of IVDD. Thus, in studies on IVDD, the enhancement of anabolism should be emphasized, and catabolism should be reduced to restore ECM homeostasis, which is of critical significance to maintain ECM integrity and slow IVDD. Recent evidence demonstrates that exosomes and exosomal miRNAs are capable of regulating the gene expression level of synthesis and catabolism of ECM and effectively storing ECM homeostasis. It has been reported that after treating IVD cells from IVDD patients with MSCs-exos for 7 days, ECM production was observed to be more than three-fold higher than that of control group, and MMP-1 expression was significantly inhibited . LikewisA wide range of adverse microenvironments can result in intracellular mitochondrial dysfunction and excessive levels of mitochondrial ROS in IVD, and antioxidative strategies such as antioxidant administration and repair of mitochondrial dysfunction may benefit the treatment of IVDD . It is oIn vivo, exosomes are capable of protecting the content of proteoglycan in IDD rabbit model, inhibiting ECM degradation, and slowing IVD progression , which can target to inhibit the activation of IGF1R/PI3K/Akt pathway for inhibiting the proliferation, migration and matrix synthesis of AFCs and facilitating the apoptosis of AFCs . FurtherSince the exosomes derived from IVD cells with abnormal degenerative phenotype can promote the progress of IVDD, a question is raised that whether we can make IVD cells release stronger exosomes through pretreatment. It seems feasible. NPCs treated with rapamycin (RAP) derived more exosomes and increased the expression of mir-27a in exosomes, which attenuate IL-1β-induced ECM degradation in NPCs by targeting MMP-13 . LikewisThe research based on miRNAs has been gradually shifting to the stage of clinical experiment. However, a drug delivery system with stronger stability, lower clearance rate, better biocompatibility and immune tolerance is urgently required, and more specific targeting effect. With the identification of exosomes as intercellular messengers, there has been intense interest in the study of exosomes. They are capable of carrying a wide variety of goods shuttle in cells, while simultaneously transmitting different signals to achieve real-time intercellular communication. The nanoscale size and special structure of exosomes make it easier for them to escape the phagocytosis of lysosomes, their contents are better protected, and they can support the distance of systemic transport. Self-derived exosomes are less immunogenic, and the presence of a hydrophilic center makes them easier to encapsulate water-soluble drugs . On thatin vivo experiments should be performed to demonstrate whether its induction efficiency is affected by the content of exosomes and the type and state of originating cells, whether the complex environment in degenerated IVD will interfere with the migration rate of recruited cells, and whether the cytokine secretion of activated MSCs will also be affected.However, the potential and advantages of this emerging treatment strategy are not significant since there are numerous problems to be solved. Combined with the existing research progress, whether we can effectively restore the number and density of cells in IVD is dependent on the stability of apoptosis, cell aging and proliferation. Likewise, most studies have been conducted. These studies have emphasized the role of exosomes and exosomal miRNAs in intervening the apoptosis, aging and proliferation of NPCs, but rarely involve AFCs (only 3 items) and CEPCs (only 3 items). It is necessary to gain a full insight into the regeneration and protective characteristics of this method on all terminal differentiation types of cells in IVD. The change of miRNAs expression profile is significantly correlated with IVDD, thus providing an opportunity for exosomal miRNAs as therapeutic targets to counteract the degradation process. Moreover, to improve the therapeutic effect of exosomal miRNAs, target miRNAs or miRNA mimics can also be directly transfected into exosomes through electroporation, ultrasound and freeze-thaw cycle  Figure . Howeverin vivo, and their biologically active functions should be maintained. The researchers built a system of thermosensitive cell-free ECM hydrogel combined with ADSCs-exos, capable of significantly maintaining the microenvironment homeostasis in early IVD and inhibiting pyroptosis of NPCs , consisting of intradiscal injection of exosome-rich autologous platelet-rich plasma in 30 participants, scheduled completion by 25 July 2022, however, no specific experimental results have been reported yet, and it is expected that this clinical trial can provide a reference for subsequent clinical trials to advance. In brief, as a novel strategy for treating IVDD, exosomes and exosomal miRNAs bring both hope and challenges. However, we consider that the solution of the above basic and clinical problems will bring great surprises to the reversal of IVDD.Exosomes and exosomal miRNAs show a wide range of promise in the field of IVDD therapy.They have been confirmed to prevent or even reverse the process of IVDD by regulating IVD cell apoptosis, restoring ECM homeostasis, reducing inflammatory response, antagonizing oxidative stress injury, and inhibiting angiogenesis. However, despite the recognized therapeutic potential, fundamental issues of exosomes and exosomal miRNAs for the treatment of IVDD remain, such as efficient and pure exosome production methods and standards, comprehensive IVD cell targeting studies, reasonable dosing and frequency criteria for administration, appropriate vector selection or pretreatment, accurate and sensitive differential expression analysis of miRNAs, and efficacy assessment of methods and criteria, all of which need to be confirmed by subsequent studies. Additionally, the fact that exosomes are cell-derived but not cellular may pose challenges to their legal classification and obtaining regulatory approval for use in clinical trials in various countries . For now


The global COVID-19 crisis exposed the critical need for a highly qualified public health workforce. This qualitative research aimed to examine public health workforce competencies needed to face COVID-19 challenges and identify the gaps between training programs and the competency demands of real-world disasters and pandemics. Through a sample of thirty-one participant qualitative interviews, we examined the perspectives of diverse stakeholders from lead public health organizations in Israel. Grounded Theory was used to analyze the data. Six themes emerged from the content analysis: public health workforce's low professional status and the uncertain future of the public health workforce; links between the community and Higher Education institutions; the centrality of communication competencies; need to improve health promotion; the role of leadership, management, and partnership, and innovation in public health coherence. Increasing the attractiveness of the profession, professional and financial support, and improving the working conditions to ensure a sustainable and resilient PH system were deemed necessary. This paper describes and cultivates new knowledge and leadership skills among public health professionals, and lays the groundwork for future public health leadership preparedness programs. The COVID-19 pandemic crisis poses unique and unchartered challenges to public health (PH) systems worldwide .Ensuring effective responses to large-scale outbreaks requires nimbly adaptive health systems capacities and strengthening public health workforce (PHW) competencies to meet population health needs . AnalyziA recent study in Korea found that PH nurses scored low in competencies clustered around the three disaster management stages: prevention stage, mitigation stage, and recovery post-disaster stage, using the Disaster Preparedness Evaluation Tool . DisasteThe COVID-19 crisis called attention to the significance of specific PH competencies in addressing the needs of vulnerable at-risk populations such as minorities, seniors and adapting recommendations and messaging to the local contexts of communities at risk . PsychosWe conducted a prospective, qualitative study as part of a multinational Erasmus Plus Capacity Building European Union-funded grant in Higher Education funded project entitled “Sharing European Educational Experience in Public Health for Israel (SEEEPHI): harmonization, employability, leadership, and outreach .Israel's health system is predominantly a public system designed to care for almost 10 million citizens . All resThirty-one mid to senior-level managers in the Israeli PH service, health funds, and hospitals were interviewed between September and December 2021. We used purposive sampling to ensure a diversity of respondents and selected to obtain maximal subjective heterogeneity and serve as rich information sources to meet the study's objectives. The sample included interviewees employed in PH and health services, health funds, and hospitals and represented all the health districts in Israel .We conducted a prospective qualitative study using a pre-tested semi-structured individual interviews using interview guides. The topics that guided the question development are the following: (1) PHW competencies needed to address COVID-19 challenges and prepare the PH system for the post-pandemic period and future health challenges; and (2) potential gaps between academic training and the demands of the PH labor market in Israel.The interview guide was based on the WHO-ASPHER Competency Framework for the Public Health Workforce in the European Region (CFPHW tool) . This vaAll interviews were conducted over the telephone due to COVID-19 social distancing restrictions and were audiotaped and transcribed verbatim in Hebrew in a standardized format. The interviewer was a Clinical Psychology graduate student, trained in qualitative research methods and supervised by the study's research staff (OB and ZM). The interviewer received the list of 35 PH managers and contacted them to explain the study's purpose and ask if they wanted to participate. Thirty-one managers agreed to participate and were given a detailed explanation of the study plan. No relationship was established between the interviewer and the study's participants before the study commencement. Each interview was audio-recorded and lasted between 40 and 60 mins. The research team discussed the emerging key themes during the interview, and data richness and some of the interviews were analyzed in parallel with the data collection. We derived new hypotheses as a result of this ongoing data analysis.All the interviews were transcribed and analyzed by two researchers (OB and ZM) using a thematic analysis method based on grounded theory . GroundeThe interview guide and study were approved by the Ashkelon Academic College Ethics Committee . Written informed consent was obtained from all participants.Twenty-one women and ten men participated in the study. Twenty-two were PH physicians (MD and MPH), four PH nurses (with MPH), three health promotion professionals, and two environmental and food inspectors. Nine interviewees worked at the regional health department, nine at the MoH, three in hospitals, three in research units, five at the headquarters units, one in a health fund, and one in the Israeli Defense Forces Medical Corps.The data analysis resulted in six main themes that emerged from the interviews: public health workforce's low professional status and the uncertain future of the public health workforce; links between the community and Higher Education institutions; the centricity of communication competencies; need to improve health promotion; the role of leadership, management, and partnership, and innovation in public health. All interviewees spoke about their concerns related to the perceived low professional status of PHW. They indicated the necessity to invest more resources in training and preserving PHW, highlighting the increased demands for disease prevention, links with excluded communities, and the need for rapid responses to new public health challenges. The decline in the PH budget in recent decades has made it difficult for the PHW to meet routine needs, and these gaps became more significant during the COVID-19 pandemic. The PH system in Israel reached its insufficiency point early during the pandemic, requiring reassigning routine PH operations to other agencies while derailing important ongoing health activities such as health promotion activities or non-COVID-19 vaccinations such as childhood immunization schedules. The cumulative impacts of years of PH system neglect allowed only limited responses to the most urgent ongoing issues while generating workforce burnout, as described by Khouri et al.  should employ many more qualified PH practitioners and engage young doctors and nurses to increase their professional exposure and competency in PH matters.The interviewees believed that the central roles that PH professionals hold in the MoH could improve the professional status of public health workers in the clinical-oriented medical community. They anticipated that more resources would follow after the post-COVID exposure, given the increased prominence of public health needs during the pandemic.Several interviewees underscored their general satisfication and devotion to their work and are content with the changes they were able to facilitate in the community while developing professionally. Many interviewees expressed serious concerns about the future of the PH profession. They offered pessimistic views about facing the gaps between the growing needs and the increasing demands for PH and considering the COVID-19 implications. Nevertheless, many highlighted the urgent need to further develop the PH profession's status.The growing importance of reciprocal partnerships between the “field” and academic higher education institutions was highlighted in several interviews. Interviewees pointed to the gaps between training and practice in the field and raised the urgency to tailor the educational training to the changing community PH needs. Public health research in health departments is currently performed as “self-initiatives” without dedicated resources. In addition, interviewees underscored that there are limited research collaborations among the different healthcare professions.Applied PH research can be an excellent opportunity to strengthen the trust, respect, and connections between academia and field practitioners while upgrading the PH system, broadening the range of competencies, and enhance professional satisfaction. Lecturers from academia teach in the PH system and establish “in-service training” for PHW staff; however, due to a lack of resources and incentives to encourage research, this mutual “fertilization” is not sufficiently taken advantage of. Interviewees suggested that continuously updating knowledge and strengthening research competencies through lifelong learning and immersive opportunities could improve the professionalism of PHW. Interviewees also recommended exposing PH students to real-world practices in the field during training by visiting organizations that provide PH services. They also suggested that teaching in academic institutions should include problem-based learning and case studies, including how to balance needs and address ethical and resource dilemmas.The interviewees indicated that PH leadership should be more dynamic and learn to adapt more swiftly to the challenges of the changing world, such as climate change and preparedness for global crises. They recommended that outreach activities with academic institutions be more attentive to the new fields of interest, including acquiring new methodological tools, both quantitative  and qualitative (including using mixed methods), and train PH students to employ versatile responses by equipping them with the appropriate tools and technologies to address new challenges, such as refugee migration and climate change.Communication competencies include informing and influencing individuals, communities, and various audiences across essential health issues . The medInterviewees also noted that PH professionals should better understand how the media works, learn to better respond to crisis events, communicate critical messages, and use practical tools to communicate effectively on different media channels. These channels include social media platforms which had a dominant role during the pandemic, as PH issues were intensely discussed on social media platforms where many misconceptions and conspiracy theories were spread .Interviewees also suggested that PH professionals should portray health messages in a culturally sensitive fashion to diverse populations. It was also mentioned that messages need to reach Israel's social and geographical rural areas.Participants addressed the need to expand health promotion practice using practical tools for ongoing interventions in the PH field. Several interviewees commented that health promotion and education expertise is not sufficiently used in addressing racism and social inequities. As a result, mistakes were made in communicating the public health-promoting messages related to COVID-19, especially to minorities, migrant workers, and other vulnerable groups.Interviewees noted that the health system is usually preoccupied with curative treatment rather than prevention efforts. Acute and chronic care overtook the resources and managerial attention needed for health education and promotion or program assessments. Several interviewees commented that more resources were needed to prevent viral transmission and identify health-related risks such as stress, loneliness, obesity, smoking, and chronic diseases. Further, they indicated that COVID-19 management should have employed a more interdisciplinary approach. They also commented that PH professionals should be more active in promoting physical activity, proper nutrition, and stress relief.Interviewees expressed concerns about the low levels of training in leadership competencies and the ability of managers to build and maintain partnerships and collaborations with other agencies in the community. They emphasized that PH training should include foundation training in management and leadership skills to enable graduates to lead change during times of crisis in the community. PH professionals should improve the links with vulnerable communities and health institutions and partner with local authorities and government agencies to identify health disparities and implement health interventions.Interviewees mentioned that PH professionals in managerial positions should have improved decision-making competencies in situations of uncertainty. PH training includes evidence-based practice and decisions supported by epidemiological findings. However, during the last two decades and especially during the COVID-19 outbreak, the need for decision-making in states of uncertainty and the need to move to informed decision-making that is shaped and focused on different kinds of evidence became evident. These changes became even more pressing as PH officers had to make swift decisions at the national and local levels based on partial and often conflicting information that became obsolete.Some interviewees mentioned that it is essential for PH leaders to acquire competencies related to political discourse, collaborate with politicians to prioritize PH issues, and lead changes at the national level with key government stakeholders and politicians.Interviewees advised that PH organizations must engender a supportive organizational culture that motivates a competent workforce and supports new technologies to address PH challenges. In particular, this should include using innovative computer-based and digital technologies to monitor and manage recurrent and emerging diseases, chronic morbidity, aging population, societal inequities, unhealthful lifestyles, climate change. They stressed, the skills needed to analyze big datasets of the health funds and hospital discharge information systems of the MoH which are well developed but underutilized in Israel. Interviewees also indicated that the limited technological infrastructure in PH was one of the primary reasons for the deficiencies of the PH system in dealing with the COVID-19 outbreak in Israel. Fostering a robust technological infrastructure is critical for rapid and professional decision-making.Our findings highlight the lack of investment in the PH workforce and infrastructure which limited the capacity of the PHW in Israel to better respond to COVID-19 due to years of system neglect, budget cuts, and lack of investment in the PH workforce and infrastructure, limiting the capacity of the PHW in Israel to respond to COVID-19 and other emerging health challenges. Our findings illustrate that PH workforce gaps became evident during the COVID-19 crisis and underscored essential competencies required to face new health challenges. Interviewees from research departments, headquarters units, and the MoH pointed to essential competencies that should be taught in PH academic programs, such as communication and health promotion, leadership, and technology-based innovation competencies. At the same time, interviewees from the regional health department and health funds pointed to training competencies that should be strengthened “on the job” with continuous education courses and employer initiatives to keep PH staff updated on current practices, including emerging research and leadership.Our findings highlight the ongoing weaknesses in the relationships between community-based workers, clinical teams, and university academics regarding shared goals, knowledge, and mutual respect. These “relational dynamics” are associated with a lack of frequent, timely, accurate, and problem-solving communication, predicting low quality and efficiency of their interactions . All IntInterviewees especially from regional health departments and headquarters units also mentioned that PH professionals should employ an integrated approach to disease prevention. Kickbusch similarly discusses the need for health promotion professionals to understand the nature of pandemics but also the nature of health decision-making around the pandemic, the roles of health organizations and communities in reaction to pandemics, and the significant effects of health promotion in the rapidly evolving management of pandemics .Leadership competencies were a key component for successful management during the COVID-19 outbreak . The curPH service leaders need to be actively involved and support research at their institutions and establish fruitful connections with other experts and institutions. Additionally, the concept of shared, evolving knowledge was raised by several interviewees, including those from hospitals and research units, demonstrating the need for the PHW to strengthen the links between practitioners in the field and academic researchers. These links were also mentioned in relation to the importance of PH students' practical experience in PH organizations during studies and have been called out in previous studies , 34.Most of the participants expressed deep concerns about the future of PH. The striking gaps between the primary positions that PH professionals hold in daily-life decisions, including managing COVID-19, and the unattractive working conditions they endure. Low incomes and prestige hinder candidates from considering public health as a career choice. These findings follow a recent examination of the US governmental PHW by Sellers et al. , who notOur study has several limitations. First, the study results reflect the Israeli health system, which may not be generalized to other countries with their distinct health delivery systems, comprising unique legislative and organizational characteristics, and within different clinical and political settings. Second, although the themes seemed consistent across the interviewees, and the influence of the varying systems on the findings was frequently discussed during the data collection and analysis, the local and specific impacts of these cultural barriers may have been under-appreciated . Third, We believe that the study considerably advances the understanding and roles of the PHW perceptions often missed in quantitative research and is valuable in presenting a more comprehensive and in-depth picture of the effects of the pandemic on PHW. The critical role of the PHW in responding to and eventually recovering from the COVID-19 pandemic emphasizes the need to strengthen PHW competencies. Capacity building of a well-qualified and competent workforce is crucial to the resilience of the PH system in times of global crisis. Improving preparedness to confront emerging health challenges requires a sustainable PHW, governmental investment in the PH system, improving the profession's prestige and work conditions, and ongoing support for strong public health leadership.Various steps are required to improve PHW competencies and globally strengthen PH systems. These include establishing a task force composed of PH services professionals and representatives of PH higher education programs to discuss ways to collaborate, redesign and better adapt educational programs to the field's needs. PH training programs should include new learning skills, encouraging innovative thinking, self-learning skills, problem-based learning , and casThe original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ashkelon Academic College Ethics Committee . The patients/participants provided their written informed consent to participate in this study.OB, RO, LL, KC, KD, TT, and ZM: conceptualization. OB, RO, LL, KC, and ZM: project administration. OB, KD, and ZM: data curation. OB and ZM: analysis, interpretation, and writing-original draft. OB, RO, LL, KC, PB, ND, KD, MD, LO, FM, YN, MR, TT, and ZM: review and editing. All authors contributed to the article and approved the submitted version.The current study is part of a multinational Erasmus+ Capacity Building in Higher Education funded project- Sharing European Educational Experience in Public Health for Israel (SEEEPHI): harmonization, employability, leadership, and outreach. The project is financed by EU funds within the framework of the Erasmus+ Programme of the European Union (Grant Agreement 618578-EPP-1-2020-1-BE-EPPKA2-CBHE-JP).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Dysphagia is one of the most common manifestations of stroke, which can affect as many as 50–81% of acute stroke patients. Despite the development of diverse treatment approaches, the precise mechanisms underlying therapeutic efficacy remain controversial. Earlier studies have revealed that the onset of dysphagia is associated with neurological damage. Neuroplasticity-based transcranial magnetic stimulation (TMS), a recently introduced technique, is widely used in the treatment of post-stroke dysphagia (PSD) by increasing changes in neurological pathways through synaptogenesis, reorganization, network strengthening, and inhibition. The main objective of this review is to discuss the effectiveness, mechanisms, potential limitations, and prospects of TMS for clinical application in PSD rehabilitation, with a view to provide a reference for future research and clinical practice. Dysphagia, defined as “difficulty swallowing,” is one of the most important clinical manifestations of stroke and a common consequence of neurological damage caused by a range of diseases . StudiesAlthough dysphagia gradually resolves spontaneously in the early stages of disease in most cases, severe and persistent forms of dysphagia remain prevalent in about 13% of stroke patients . The preStudies have demonstrated that central causes of dysphagia in stroke patients include cortical or brain-stem damages, and peripheral causes include damages to the nerves or muscles involved in swallowing. The brain-stem lesions are more commonly associated with dysphagia . NotablyThe treatment options of PSD include behavioral therapy, oral care, pharmacology, neurostimulation, and dietary interventions. Various physical therapies and preventive measures can avoid dysphagia-related complications. However, there is a lack of medical or electrophysiological interventions to facilitate recovery from dysphagia after acute or subacute stroke.Existing treatments for PSD include postural training , dietaryAccording to a previous study, the pathogenic cascade of dysphagia is as follows: after peripheral or central (corticobulbar tract) impairment of the cranial nerves innervating the swallowing muscles, tongue movement is limited, with soft palate paralysis. Consequently, intraoral and pharyngeal pressure cannot be fully increased, movement of food from the oral cavity to the pharynx and esophagus is weak, and transit time is significantly prolonged. The retention increases hyperreflexia or spasm of sphincter and cricopharyngeal muscle in the esophageal inlet of patients with supraglomerular damage  and movement of the swallowing muscles is uncoordinated, resulting in accidental ingestion of food into the trachea . In receTranscranial magnetic stimulation is a non-invasive stimulation technique based on the principles of neuroplasticity that induces changes in neurological pathways by altering neurons in target cortical areas through synaptogenesis, reorganization, network strengthening, and inhibition, causing local depolarization of the magnetic field below the skull and activation or inhibition of activity in cortical areas . It was via modulation of neuroplasticity. The procedure is based on the principle of inductance and non-invasively transmits electrical energy to the brain through the scalp and skull (N-methyl-D-aspartate (NMDA) receptors, as revealed by studies using NMDA antagonists  caused dysphagia, possibly due to disruption in the sensorimotor pathways of the corticobulbar tract. TMS may exert effects on PSD by regulating sensorimotor pathways in the brain. However, the details of how TMS change the communication and connection of cortical neural networks to achieve the therapeutic effect remain largely unexplored. The advantages and disadvantages of TMS were shown in Transcranial magnetic stimulation is widely regarded as a safe and non-invasive form of nerve stimulation that can be used to directly manipulate cerebral cortex activity. In recent years, this innovative neuromodulation technology has been widely applied in neuroscience and countless cognitive fields  and showDespite the considerable benefits of TMS, lots of limitations restrict its use in clinical practice in terms of effectiveness, safety, and clinical study design. First, no significant beneficial effects of TMS on genetic factors, death, dependence, disability, prognosis, or length of hospital stay have been reported . Second,This review provides a summary of the efficacy and underlying mechanisms of TMS activity in patients with PSD. A large majority of studies to date has used water-swallowing test (WST), clinical dysphagia scale (CDS), Dysphagia Outcome and Severity Scale (DOSS), Permeation Aspiration Scale (PAS), Mann Assessment of Swallowing Ability (MASA), Videofluoroscopic Dysphagia Scale (VDS), representative pharyngeal motor evoked potential (PMEP) amplitude, cumulative penetration-aspiration score (cPAS), and degree of dysphagia (DD) to evaluate the significance of the results. However, given the evidence for the validity of the results, it may be possible to incorporate more credible tests to draw strong conclusions in future studies. In 1993, Hoshi and Tamura demonstrated the validity of measuring different cortical regions with functional near-infrared spectroscopy (fNIRS). For the first time, the potential of fNIRS imaging brain activation sequences were reported . fNIRS iAll authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.


Dugong dugon) resides in the coastal waters of the United Arab Emirates, and waters surrounding Saudi Arabia, Bahrain, and Qatar. The archaeological record of dugongs in the Gulf Region is abundant, but little is known about their fossil record in the region. Here we report an isolated sirenian rib fragment from the Futaisi Member of the Fuwayrit Formation near the town of Al Ruwais, in northern Qatar. The Fuwayrit Formation is a marine Pleistocene deposit exposed onshore in Qatar and the United Arab Emirates. Based on the correlative dating of the basal Futaisi Member with other onshore platforms, the rib fragment is approximately 125 ka. We propose that this isolated rib (likely the first rib from the right side) belongs to Dugongidae, with strong similarities to extant Dugong. We cannot, however, eliminate the possibility that it belongs to an extinct taxon, especially given its similarities with other fossil dugongid material from both Qatar and elsewhere in the world. Aside from reflecting the presence of Gulf seagrass communities in the Pleistocene, this occurrence also suggests that different  lineages of sirenians inhabited the Gulf Region in the geologic past.One of the largest and least documented populations of dugongs ( Dugong dugon  in the ng dugon . The Gulng dugon . Howeverng dugon . Historing dugon , althougng dugon  has provNearshore marine deposits throughout the Gulf Region  provide Dugong. Fossil Dugongidae from the eastern Tethys are less well known, but provide striking evidence for multispecies sirenian communities that occur globally during the Cenozoic , Hydrodamalis gigas , Priscosiren atlanticaProtosiren sattaensisProtosiren smithaeTrichechus inunguis .Stratigraphy, depositional environment and age. The modern-day peninsula of Qatar is the result of Arabian-Eurasian tectonic plate convergence in the Neogene and the Zagros orogeny in modern-day Iran during the Plio-Pleistocene. This tectonism created fold-thrust belts in Iran and a wedge-shaped, low angle foreland basin in the Gulf Region with mixed evaporites, carbonates, and siliciclastics deposited on the Arabian plate, along with several depositional hiatuses caused by Neogene sea-level change  and Dammam (Lutetian) formations . The Dami.e., angular, poorly sorted dolomitic clasts), which are set in a matrix of marine allochems and micrite  setting. The degree of bioturbation reflects the difference between predominantly subaqueous and predominantly subaerial settings. The most heavily burrowed sediments were frequently submerged, whereas the wavy laminated sediment was probably deposited high up the beach, and rarely flooded afterwards. The interpretation of a foreshore environment is also supported by the recognition of a grain-contact meniscate cement as the earliest cement generation in some samples.The Futaisi Member has been interpreted as a transgressive deposit recording only the peak of a Pleistocene high-stand . The lowDating the age of Pleistocene deposits in the Gulf Region is challenging. Luminescence dating of Ghayathi Formation aeolianites from localities outside of Qatar produced age ranges between 45 and 130 ka , although these dates are likely distorted by diagenetic contamination; similar techniques on sediments from the Fuwayrit Formation have been unfruitful . Williame.g., isostatic rebound), or the onshore deposits are unaffected by tectonism. Based on the elevation and stratigraphy of the Fuwayrit Formation compared with other onshore Pleistocene platforms in Bermuda, the Bahamas, the Mediterranean, New Caledonia, Hawaii, the eastern United States, and Australia, Lacking direct age dates for the Fuwayrit Formation, Description. The rib fragment (QM.2021.0504) is about 112 mm long in a straight line, 31 mm wide at its greatest lateral extent and 17 mm thick at its thickest anteroposterior direction. The fragment is missing its proximal-most processes, including the neck and capitulum, but it appears to preserve the distalmost termination of the rib  but marks a change in surface topography, is likely part of the angle. Its distal surface likely provided an attachment for the serratus magnus and scalenus muscles  in the proximal half of the rib, which is especially visible on the external surface, and increases posteriorly from the first rib throughout the series.As for its taxonomic identity, the rib fragment does not belong to Dugong, based primarily on the anteroposterior flattening of the rib shaft and the morphology of the raised prominence, which is preserved in the Qatari specimen. In the first and second ribs of Dugong, the raised prominence marks a boundary for the changes in organization of muscle attachments: on the first rib, attachments for the scalenus and serratus magnus muscles are located distally on the dorsolateral edge, while proximally the neck and head of the rib anchor the longus capitis muscle medially, and the longissimus dorsi and iliocostalis thoracis muscles laterally; on the second rib, the prominence continues providing an attachment for the scalenus and serratus muscles distally, and the longissimus dorsi and iliocostalis thoracis proximally  of the first and second ribs of fossil and extant sirenians, including living and historically extinct sirenians , and any relevant fossil taxa, including fossil dugongids , and stem sirenians such as Pezosiren, Protosiren and an unnamed taxon of prorastomid  and the Eastern Tethys . The Nosy Makaby dugongid assemblage from Madagascar represents a slight deviation from this pattern with three dugongines and one halitherine, although we note that the broad and unconstrained temporal range of this assemblage hinders a more precise understanding of their potential ecological co-occurence. The subsequent collision of the Eurasian and Arabian plates during the mid to late Miocene eliminated this oceanic connection, and sirenians in the Mediterranean evolved along separate paths from lineages along the coasts of Africa, Arabia, and southwestern and southeastern Asia. Understanding the identity and potential diversity of sirenians from Qatar, which was located along the southern margin of the Zagros Basin on the Arabian Plate during the early Miocene, would bear on the evolution of sirenian assemblages in the Tethys in the Neogene.In the early Miocene, the Zagros Basin connected the Western and Eastern Tethys across the Eurasian and Arabian plates, and the current sirenian fossil record shows mostly non-overlapping taxonomic assemblages of halitheriine dugongids from the Western Tethys  rib (A), compared with the osteology and myology of the first (B) and second (C) ribs in Click here for additional data file.10.7717/peerj.14075/supp-2Supplemental Information 2Includes description of reports in the gray literature, references, and correspondence regarding collecting authorization.Click here for additional data file.10.7717/peerj.14075/supp-3Supplemental Information 3Supplemental dataset of first and second rib measurements from fossil and extant sirenians, including abbreviations. See main text for museum collection abbreviations. All measurements in mm.Click here for additional data file.


Introduction, paragraph two. The corrected paragraph appears below.In the original article, there was a typo error for two words, suppressed and non-suppressed, which were used in place of each other in the section Introduction. Further, an accidental deletion of a part of that sentence happened during editing of the final version of the manuscript before communicating to the Journal, which changed the meaning of the sentence. A correction has been made to Rhizoctonia solani anastomosis group (AG) 8 results in substantial crop losses, including wheat and barley. In the absence of resistant cultivars to this pathogen, biological disease suppression may act as an impressive control mechanism. A thorough investigation of taxonomic and functional characteristics of the soil microbiome is therefore required to decipher the potential biocontrol agents. Through transcriptomic analysis of wheat plants grown in fields with suppressive and non-suppressive capacity against R. solani, Hayden et al. (Arthrobacter spp. and Pseudomonas spp. as dominant taxa in the non-suppressive samples and Stenotrophomonas spp. and Buttiauxella spp. as dominant taxa in the suppressive samples. A higher expression of polyketide cyclase, many cold shock proteins, and a terpenoid biosynthesis backbone gene was observed in the suppressive samples, whereas the non-suppressive samples exhibited relatively greater expression of certain antibiotic genes and genes involved in mitigating oxidative damage (Hayden et al., “The ecophysiology of plant-microbe interaction is very complicated and interwoven. Therefore, a thorough understanding of the fine-tuning and integration of multiple signals generated through plant-microbe interactions is required for sustainable crop improvement. Under the natural environment, plants are exposed to a myriad of biotic and abiotic stresses; therefore, the defense responses of plants are very complex. Plant-microbe interactions can result in the prioritization of certain physiological, biochemical, and molecular pathways in plants, the dissection of which requires the application of multi-omics approaches. Using genomic, transcriptomic, proteomic, and metabolomic approaches entwined with bioinformatics have been successful in addressing microbial communities and functions within a given environment at a deeper level (de Castro et al., n et al.  observedThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


WHO). Although advances in diagnosis and treatment have led to significantly increased patient survival over the last decade for some cancer types, several highly aggressive cancers remain as unmet clinical needs. These cancers share common features, including resistance to radiotherapy and chemotherapy, rapid relapse after treatment, and metastasis formation. The presence of a specific subpopulation of malignant cells with tumor- and metastasis-initiating properties, such as cancer stem cells (CSCs), has been credited as the cause of these features.Cancer accounted for nearly 10 million deaths worldwide  in 2020 . In the TME, several microenvironmental  and cell-autonomous  factors, coupled with bidirectional cross-talk among cells, cooperatively promote stemness, tumor progression, metastasis, therapy resistance, and tumor relapse.The scientific community has tried for decades to understand cancer behavior in the context of therapeutic strategies. The idea that cancer aggressiveness may rely on CSCs that share features of normal stem cells has changed the perspective with regard to new therapeutic approaches. In this regard, the study of the TME (or CSC niche) has become essential, due to the TME’s capacity to induce metabolic reprogramming of CSCs . These unique metabolic features of CSCs make them essentially different from normal stem cells and also represent excellent potential therapeutic targets.This article collection highlights the essential role of cellular metabolism for prognosis, tumor progression, and CSC targeting in aggressive cancer types such as melanoma, pancreatic adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), and glioblastoma (GBM). This issue includes four articles representing the work of more than 30 authors in the field of cancer research.Chisari et al. discuss in their review, both glucose and amino acid metabolism are rewired to meet cancer cells’ needs as they are challenged with lack of nutrients during tumor growth. The review focuses on PDAC, HCC, and GBM, three of the most aggressive types of tumor. Cancer cells from different origins can demonstrate specific amino acid requirements and become dependent on non-essential amino acids, which are therefore termed conditionally essential amino acids. One example is glutamine, which is essential for proliferation, redox regulation, and purine and pyrimidine biosynthesis. Similarly, the metabolism of tryptophan, an essential amino acid, supports not only tumor cells but also stromal cells, which use its byproducts for their own nucleotide synthesis; moreover, the expression of the enzymes that metabolize tryptophan has been correlated with worse prognosis and immune suppression. These and many other examples are reviewed in Chisari et al.; ultimately, they emphasize that targeting amino acid metabolism has the potential to improve the survival of patients suffering from the most aggressive cancer types.Amino acids are vital nutrients for the survival of all cell types; in cancer, their metabolism is reprogrammed to facilitate the proliferation of cancer cells under stress conditions. Moreover, amino acid derivatives contribute to the immune responses and epigenetic regulation observed in tumor progression. As Cecchi et al. demonstrate how treatment with dexamethasone, a synthetic glucocorticoid, could be detrimental in patients with melanoma. They report that dexamethasone induced the expression of tryptophan 2,3-dioxygenase (TDO), the enzyme responsible for the conversion of tryptophan to kynurenine, and TDO was then found responsible for the induction of stemness properties in melanoma cells. This article highlights the need to better understand the effects of dexamethasone in melanoma, as TDO is known to promote immune escape, and as these authors have now shown, it can also promote cancer stem cell properties.Tian et al. have identified a novel hypoxia/stemness-based gene signature with prognostic value in PDAC, composed of eight genes . Most interestingly, the authors pinpoint an association between risk scores and the expression of immune checkpoint genes, suggesting that patients in the low-risk group might be more likely to respond to immune checkpoint inhibitors. These results reinforce the connection between tumor metabolism, CSCs, and the immune system, as revealed by bioinformatic analyses, a discipline with increasing significance for cancer research.Over the past few years, a growing number of articles have described the diverse mechanisms by which a hypoxic TME promotes stemness in different cancer types. This is especially relevant in PDAC, where strong desmoplasia impairs nutrient and oxygen distribution, creating a starved and hypoxic microenvironment. Hu et al. highlights recent advances in this field, including the role of lipid uptake and storage in lipid droplets, lipid catabolism through lipolysis and fatty acid oxidation, modifications through the desaturation or peroxidation of CSCs, as well as the influence of lipid signaling on the CSC niche. In general terms, with the exception of lipid peroxidation, lipid metabolism supports stemness and progression and correlates with poor prognosis in a variety of cancers. However, the role of lipid metabolism in normal stem cells, as well as the heterogeneity of CSCs in different cancer types, remains poorly understood. The authors also identify targeted delivery, the side effects of lipid-targeting drugs, extracellular signaling based on lipids as future avenues of research.The study of lipid metabolism in the context of cancer stemness and aggressiveness has attracted a lot of attention in recent years. The review by In conclusion, the articles included in this topic reflect the evolution of the field of cancer metabolism in recent years, highlighting the tumor cells’ use of alternative substrates such as aminoacids and lipids over glucose and the key role of metabolism in regulation of the immune system.


Pancreatic surgery is one of the most technically challenging types of surgery, and many questions remain unanswered; therefore, an overview of the global advancement in surgical research and clinical practice is fundamental in this field.As there is a global consensus that pancreatic surgery is a major clinical procedure, it requires adequate expertise and experience ,2,3.Several surgical techniques and different anastomoses for the reconstruction of the digestive system have been performed over the years. Generating reports within a uniform, standardized framework plays an important role in this field of research. A classification system was proposed by the International Study Group of Pancreatic Surgery (ISGPS) in 2010. They underline the importance to report factors related to the pancreatic remnant , and the pancreatoenteric anastomosis, such as the use of pancreatojejunostomy/pancreatogastrostomy, duct-to-mucosa anastomosis, invagination (dunking) of the remnant into the jejunum or stomach, and the use of a stent across the anastomosis .The available data do not show any definitive advantages for one specific type of gastrointestinal reconstruction technique after pancreatoduodenectomy, compared with other techniques ,6,7.Pancreatic surgery has been adapted to treat different pancreatic diseases .Pancreas transplantation is a curative treatment for type 1 diabetes mellitus. Current evidence shows that it has the highest complication rate among organ transplants. There is still little evidence regarding the best option for revascularization of the transplanted organ, and therefore, randomized trials are important in this field .Various factors influence cancer recurrence, morbidity, and mortality after pancreatic surgery. Some of these are known, while others have been poorly studied. The evaluation of nutritional status has gained increasing attention, especially in recent years, indicating that it should be part of routine preoperative assessment .The most common and clinically relevant complications are related to pancreaticojejunal anastomosis. In addition, the risk of postoperative pancreatic fistula , bile leResectability criteria, as well as absolute and relative contraindications to pancreatic surgery, are re-evaluated in light of new scientific evidence.Advanced techniques of surgical resection and vessel reconstruction can allow curative-intent surgery in borderline resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC).Elaborated techniques of surgical resection and vessel reconstruction have been performed to enhance the completeness of resection and reduce the risk of local recurrences, which include artery-first and uncinate-first approaches, dissection of the anatomical triangle between the coeliac and superior mesenteric arteries and the portomesenteric vein, and radical antegrade modular pancreatosplenectomy. Advanced techniques for resection and reconstruction of the mesenteric–portal vein axis and a venous bypass graft-first approach can allow resection of PDAC with venous involvement. Arterial involvement does not preclude surgical resection but may become surgically manageable following neoadjuvant treatment .A consensus statement by ISGPS establishes that current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis. It also supports exploration to confirm the imaging-based findings in the case of suspicion of arterial involvement .Although pancreatoduodenectomy (PD) with the resection of portal–mesenteric vein axis has significantly increased the resection rate in patients with pancreatic head adenocarcinoma, it seems to have lower survival outcomes and higher 30-day mortality, compared with standard PD, whereas postoperative morbidity rates are similar .More investigations are needed on the effects of surgical resection and vessel reconstruction on overall survival .Furthermore, the choice between neoadjuvant therapy and upfront surgery is debated, in particular in the case of vascular reconstruction.Emergency pancreatic surgery is rarely reported in the medical literature. However, emergency pancreatoduodenectomy can represent a life-saving procedure for complex pancreaticoduodenal injuries in selected patients.There are still many unanswered questions, and further studies are needed to better manage and treat surgical patients with pancreatic disease.Sharing researchers’ experiences and discussing surgical approaches are fundamental to providing an overview of the global advancement of surgical research and clinical practice in the field of pancreatic surgery.


In aging society, osteoporotic fractures have become one major social problem threatening the health of the elderly population in China. Compared with conventional fractures, low bone mass, bone defect and retarded healing issues of osteoporotic fractures lead to great difficulties in treatment and rehabilitation. Addressing major concerns in clinical settings, we proposed the “three in one” bone repair strategy focusing on anti-osteoporosis therapies, appropriate bone grafting and fracture healing accelerating. We summarize misconceptions and repair strategies for osteoporotic fracture management, expecting improvement of prognosis and clinical outcomes for osteoporotic fractures, to further improve therapeutic effect and living quality of patients. Osteoporosis is a systemic metabolic bone disease characterized by decreased bone strength and increased risk of fracture. Osteoporotic fractures refer to fractures caused by force that does not usually cause fractures . Data frOsteoporotic fractures are the inevitable outcome of long-term and sustained bone loss, which is a major cause of death and disability among the elderly, and brings huge social and economic burdens. In aging society, one osteoporotic fracture occurs every 3 seconds in the world, and about 50% of women and 20% of men have their first osteoporotic fracture after the age of 50 . Due to Osteoporotic fractures are often dealt with surgeries. But there are three major misconceptions currently popular among orthopedic surgeons in China: insufficient understanding of the primary disease osteoporosis, lacking concept of abnormal bone metabolism environment in osteoporosis, and underestimating bone grafting in surgery. Thus, the clinical outcome is often unsatisfactory.The author summarized over 20 years of experience in diagnosis and treatment of osteoporotic fractures, and proposed the “Three-in-one” bone repair strategy, emphasizing the concept of vigorous anti-osteoporosis, proper bone grafting and promoting bone healing, and expects to further improve the diagnosis and treatment efficacy and the quality of life of patients.Compared with fractures due to high-every trauma, osteoporotic fractures show following features: (1) It is more common in the elderly, has more complications, and is difficult to manage and recover; (2) During the fracture, immobilization or reduced exercise results in rapid secondary bone loss; (3) Common bone defects due to compression lead to difficulty in surgical reduction and stability; (4) Improper internal fixation leads to loss of internal fixation failure; (5) The risk of delayed fracture union or nonunion is higher; (6) The risk of re-fracture is significantly increased. However, there are three major misconceptions in the current clinical treatment of osteoporotic fractures.Osteoporotic fractures result from chronic bone loss due to osteoporosis. Abnormal bone metabolism and weakening of bone formation ability in the body substantially delay the healing of fractures. In the process of diagnosis and treatment of elderly osteoporotic fractures, orthopedic surgeons should fully pay attention to the negative effects of osteogenesis/osteoclastogenesis imbalance on fracture healing. At present, the Chinese people’s awareness of osteoporosis is generally insufficient. Among those >50 years old, the proportion of people who have undergone bone density testing is 3.7%, and the proportion of people with low bone mass is 57.4% . In addiBone maintains dynamic balance coordinated by osteoclast-mediated bone resorption and osteoblast-mediated bone formation . FluctuaIn patients with osteoporosis, the weakening of bone density and the binding force of the bone-implant interface directly leads to the decrease of screw holding, which increases the risk of internal fixation failure. Abnormal bone metabolism around the screw increases the incidence of internal implant cutting. In addition, low-strength cortical bone and high-porosity cancellous bone structures tend to form large-area bone defects when fractures occur, which also poses challenges to the initial stability of internal fixation. At present, orthopedic surgeons have not paid enough attention to the concept of bone grafting in reduction and fixation, and the stability by internal fixation is insufficient, which is likely to cause the later internal fixation failure and even a second fracture .In the context of chronic bone loss and decreased bone formation ability, the healing rate of osteoporotic fracture patients decreases. Immobilization-related complications by delayed union also inhibit fracture healing. In order to break this vicious circle, orthopedic surgeons should focus on maintaining bone quality, repairing bone defect and promoting bone healing, which will systematically optimize the diagnosis and treatment of osteoporotic fractures.Osteoporotic fracture is the most severe complication of osteoporosis. The treatment is to promote and accelerate fracture healing. In the past decade, 915 cases of hip fracture aged over 80 years old have been treated in the department of orthopedic trauma of the First Affiliated Hospital of PLA Naval Medical University. All patients achieved a satisfactory prognosis with the guidance of systematic and personalized treatment, including general status adjustment, appropriate implant and enhanced fracture union during the perioperative period .To solve this, the authors summarized the “Three in one” bone repair strategy based on clinical experiences and basic researches, focusing on the baseline bone mass, bone deficiency management and fracture union, and correcting misconceptions in cognition, concept and technique. It is believed that patients with osteoporotic fracture could obtain a better quality of life and a better prognosis through vigorous anti-osteoporosis, appropriate bone grafting and accelerated fracture healing, which are the three core matters of “Three in one” bone repair strategy Figure 1Intervention of perioperative period bone loss has been well recognized by surgeons all around the world , 13. Bon3  mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.  is essential for osteoclast formation and bone remodeling , 70. NevVarious mesoporous biomaterials are exploited and applied as efficient nanocarriers to loading drugs by virtue of their large surface area, high porosity, and prominent biocompatibility. Herein, recent progress and assembly mechanisms on mesoporous inorganic biomaterials are summarized systematically, and typical functionalization methods for nanocarriers are also discussed in depth. Particularly, structure-activity relationship and the effect of physicochemical parameters of mesoporous biomaterials in DDS application are overviewed. As one of the important development directions, advanced stimuli-responsive DDSs are highlighted. Finally, the prospect of mesoporous biomaterials in disease therapeutics is stated, and it will open a new stage for the development of mesoporous nanocarriers .in vitro and inhibit osteoporosis in an ovariectomized mouse model. Our findings suggest that EC-Exos may be utilized as a bone targeting and nontoxic nanomedicine for the treatment of bone resorption disorders -secreted exosomes (EC-Exos) in bone homeostasis is not well understood. Herein, we found that EC-Exos inhibit osteoclast activity isorders .via surface display of CXCR4 and a promising anabolic therapeutic approach for age-related bone loss  characterizes many pathological bone loss conditions , 75. Strone loss . Based oone loss , 77.in vitro with the help of tissue engineering technology, can simulate the complex biological functions of organs in vivo. Once proposed, it shows broad application prospects in the research of organ development, drug screening, mechanism study, and so on. As a complex and special organ, bone organoid construction itself is quite challenging. In this study, we introduced the characteristics of bone microenvironment, the concept of organoids, focused on the research progress of bone organoids, and proposed the strategies for bone organoid construction, study direction, and application prospects  (Consensus 1) , ChineseWe believe that the perioperative period is critical for orthopedic surgeons to manage osteoporosis and osteoporotic fractures. In view of the current misconceptions in osteoporotic fracture treatment, our team published Consensus 2, which elaborates the surgical protocols, rehabilitation time points and complication management of osteoporotic fracture treatment, and emphasizes the necessity and strategies of perioperative anti-osteoporosis treatment widely recognized in clinical practices . With reOsteoporotic fracture is not just a simple local fracture, but a manifestation of abnormal systemic bone metabolism. In the clinical diagnosis and treatment of osteoporotic fractures, the lack of understanding of the primary disease, bone metabolism environment, and the technical underestimation of bone grafting leads to unsatisfactory prognosis.Osteoporotic fractures heal slowly, and long-term bed rest accelerates bone loss, forming a vicious circle. The key to breaking the vicious circle is to accelerate bone healing. China has entered an aging society. With the aging of the population and the improvement of quality of life, elderly patients with osteoporotic fractures urgently need faster and better treatment. Orthopedic surgeons need to understand the abnormal state of bone metabolism, choose the appropriate implants for fracture fixation, and appropriately use bone healing materials and rehabilitation aids to accelerate fracture healing under the concept of “Three in One” bone repair strategy. The purpose is to improve the clinical prognosis of elderly patients with osteoporotic fractures.XC, YH, and ZG contributed equally to this work. JS conceived the manuscript. XC, YH and ZG wrote the manuscript. JS and XC reviewed and edited the manuscript. All authors listed have made a substantial, direct and intellectual contribution to work, and approved it for publication.This project was supported by the National Key R&D Program of China (2018YFC2001500); National Natural Science Foundation of China .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Abdominal infection combined with pneumoperitoneum after renal transplantation is rare, clinically confusing, and easily misdiagnosed by physicians as gastrointestinal perforation.A 54-year-old man experienced abdominal pain and distension together with signs of peritoneal irritation after cadaveric renal transplantation. CT and standing abdominal plain film showed a large pneumoperitoneum in the abdominal cavity and the patient underwent an exploratory laparotomy but no gastrointestinal perforation was found.No gastrointestinal perforation was found during the operation. In the search for the infectious agent, ascites culture was negative while next-generation sequencing was positive, suggesting the presence of intestinal flora ectopic to abdominal infection with anaerobic respiration fermentation leading to large amounts of gas.The patient underwent exploratory laparotomy without gastrointestinal perforation, and then underwent abdominal lavage, placed abdominal drainage tube, and conducted culture and next-generation sequencing examination of ascites.Postoperative symptoms were relieved and intestinal function recovered. After 3 months of outpatient follow-up, the patient had stable transplanted kidney function and was in good spirits and sleeping well, with a good appetite, soft and regular stools, no abdominal pain and distension, and no fever.Patients after kidney transplantation should be wary of abdominal infection being misdiagnosed as gastrointestinal perforation. However, there are few reports on pneumoperitoneum secondary to abdominal infection after renal transplantation, and easily misdiagnosed by physicians as gastrointestinal perforation. We describe a case of abdominal infection combined with pneumoperitoneum that occurred soon after renal transplantation.Severe intra-abdominal infections are common and significant problems in the intensive care unit, and the abdomen often ranks first among the sources of infection or sepsis. Peritonitis is generally classified as primary, secondary, or tertiary.A 54-year-old man was admitted to the hospital with the complaint of “maintenance hemodialysis for 7 years,” and was diagnosed with “renal end-stage renal disease,” with a previous history of “coronary atherosclerotic heart disease.” The patient underwent cadaveric donor allogeneic kidney transplantation, with the transplanted kidney placed in the left iliac fossa. He was then treated with ATG + glucocorticoid induction therapy, a triple prophylactic anti-rejection regimen of cyclosporine + Mycophenolate Mofetil + prednisone, as well as anti-infection therapy with meropenem. The urine output was insufficient in the early postoperative period, so hemodialysis was performed once on the third postoperative day, after which the patient’s urine output gradually increased and the blood creatinine level began to decrease.The patient had 1 black stool on the eighth postoperative day, although his blood pressure and hemoglobin remained stable. The following day, the patient developed abdominal pain and distension, and physical examination of the abdomen revealed both pressure and rebound pain, while the right lower abdomen was slightly obvious, without fever. The abdominal CT was repeated and revealed a newly emerging pneumoperitoneum (Fig. There was a large amount of gas in the abdominal cavity, as well as about 500 mL of yellow pus. Irregular inter-intestinal abscesses were visible in the right lower abdomen and pelvic cavity, with a large amount of pus moss attached to the surface of the intestinal canal, together with congestion and edema of the intestinal wall. Exploration showed no perforation of the stomach, duodenum, small intestine, colon, or rectum; the appendix was unevenly thickened, hard in texture, congested and edematous, and no perforation was observed. After joint consultation between the general surgery, organ transplantation, gastroenterology, and infection departments, it was unanimously agreed to remove the appendix. The abdominal cavity was flushed, and colonic paracolic drains and pelvic drains were placed for drainage.Proteus vulgaris, Bacteroides ovatus, Rumen bacteria, Enterococcus faecium, and Bifidobacterium longum. After further treatment, the creatinine level finally decreased to 99 µmol/L by the time of discharge. As infection and dehiscence of the wound occurred after exploratory laparotomy, debridement and suturing were performed after dressing changes to control the infection, with the removal of sutures 4 weeks after surgery, at which time the wound had healed well. After 3 months of outpatient follow-up, the patient had stable transplanted kidney function and was in good spirits and sleeping well, with a good appetite, soft and regular stools, no abdominal pain and distension, and no fever.After the operation, the patient was transferred to the intensive care unit. The patient then developed fever, with elevated levels of urea nitrogen, serum creatinine, and serum potassium. He received blood purification treatment to remove metabolic waste and inflammatory factors. The oral anti-rejection drugs were discontinued at the same time, while methylprednisolone 40 mg/d was given intravenously together with imipenem-cilastatin anti-infection treatment and nutritional support. The anus was deflated on the second postoperative day. He was transferred back to the general ward 4 days after the operation, showed yellow stools, and received diet restoration and triple anti-rejection therapy. The patient’s temperature returned normal on the seventh postoperative day. The abdominal drainage tube was gradually removed on the eighth postoperative day, and repeat CT showed a significant reduction in the pneumoperitoneum compared with the preoperative pneumoperitoneum Fig. C. Postop The vast majority of kidney transplants do not enter the abdominal cavity, so abdominal infections rarely occur in kidney transplant recipients without peritoneal dialysis tubing. Abdominal infections are reported to occur most commonly after liver transplantation. The abdominal infection seen in this patient is a rare occurrence and was thus worth exploring as the abdominal cavity had not been invaded during the renal transplantation and he had no previous history of peritoneal dialysis.Patients’ bodies are adversely affected by end-stage renal disease and its complications, as well as postoperative immunosuppressive therapy, resulting in immunocompromise. Kidney transplantation recipients are at high risk of infection from pathogens including viruses, bacteria, and fungi, with sites of infection commonly found in the respiratory, urinary, and gastrointestinal tracts, as well as at the site of the surgical incision. The intestinal flora and the body are in a dynamic balance and maintain the health of the body; disruption of this balance is often manifested as a decrease in the proportion of beneficial bacteria, overgrowth of pathogenic bacteria, conversion of conditionally pathogenic bacteria into pathogenic bacteria, and promotion of disease progression. Beneficial bacteria in the intestinal tract enhance the barrier function of the gastrointestinal mucosa by adhering to the intestinal epithelium, forming a micro-ecological barrier to prevent colonization and invasion of the epithelium by pathogenic bacteria. In this case, carbapenem broad-spectrum antibiotics were started early postoperatively, which may have led to the killing of sensitive flora in the intestine and greatly reduced the number and diversity of probiotic bacteria, thus allowing colonization and proliferation of pathogenic bacteria, resulting in a microecological imbalance. NGS of the patient’s peritoneal fluid revealed that the infecting bacteria in the peritoneal cavity belonged to the normal human intestinal flora. It is likely that disruption of intestinal defense associated with the underlying disease and the use of high doses of corticosteroids and other immunosuppressive drugs during the perioperative period of transplantation, led to the presence of ectopic intestinal flora and abdominal infection. It is worth noting that NGS was able to detect the ectopic bacteria while the ascites culture was negative. NGS allows the simultaneous sequencing of thousands to billions of DNA fragments and can amplify and detect free DNA and DNA fragments in dead cells, making it possible to quickly identify pathogens in culture-negative specimens. This highlights the practical value of NGS in the detection of pathogens when traditional bacterial detection is ineffective. Culture negativity may also have been associated with the use of carbapenem antibiotics immediately after surgery. When anaerobic bacteria translocate from the intestine to the abdominal cavity and cause infection, they will produce large amounts of carbon dioxide gas through anaerobic respiratory fermentation, which explains the large amount of gas observed in the abdominal cavity by CT.The intestinal flora represents the largest micro-ecosystem in the body, with about 1014 bacteria residing in the intestine. These bacteria belong to 30 genera and 500 species and are mainly composed of anaerobic, facultative anaerobic, and aerobic bacteria, among which Lactobacillus and Bifidobacterium are the principal specialized anaerobic bacteria, together accounting for about 95% of the intestinal flora. The presence of right lower abdominal pressure rebound pain and pneumoperitoneum inclined the physician to suspect appendicitis and gastrointestinal perforation; however, the findings of both the surgical exploration and postoperative pathological analysis ruled out the above. Due to the high mortality rate in patients with the gastrointestinal perforation complication of peritonitis without aggressive surgery, even if the preoperative diagnosis is not completely precise, aggressive surgery is more likely to be the preference of general surgeons, while abdominal irrigation and drainage also play a positive role in controlling infection, albeit at the cost of surgical strikes and wound infection. In the last century, with the continuous development and maturation of laparoscopic techniques, laparoscopic exploration has been widely used for the early diagnosis and treatment of acute abdominal disease. In this case, the general surgeons were concerned about the effect of abdominal pressure on the transplanted kidney and the restriction of the transplanted kidney to the position of the trocar, together with other factors, and an open surgical plan was finally used. While successful cases of the laparoscopic management of abdominal disease in patients after renal transplantation have been reported, the number of cases is small, and the accumulation of successful experience has the potential to make laparoscopic surgery a preferred option for the management of abdominal disease in renal transplant recipients.The patient presented with peritonitis after the onset of the disease, but without fever and shock, which may be attributed to the use of glucocorticoid. Cortisol has a clear inhibitory effect on pro-inflammatory mediators, and inhibits endothelial cells and neutrophil activation, thus blocking the acute phase response.Conceptualization: Hongwei Zhang.Data curation: Huachen Zhu.Investigation: Zhiming Deng, Huachen Zhu, Wei Du, Hongwei Zhang.Methodology: Zhiming Deng.Validation: Hongwei Zhang.Visualization: Zhiming Deng, Wei Du.Writing – original draft: Zhiming Deng.Writing – review & editing: Hongwei Zhang.


Over the last few decades, significant progress has been made in the understanding of cognitive and behavioral involvement in patients with amyotrophic lateral sclerosis (ALS). In this Frontiers Research Topic, the seven articles contributing to this special theme will help readers overcome the traditional concept of ALS being a disorder exclusively affecting only the motor system of the neuromuscular system, as well as frontotemporal dementia (FTD) being more than just a form of dementia, through novel neuroimaging, neuropsychological, and epidemiological studies.Devenney et al. identify a similar pattern of neuropsychiatric symptom severity in a mixed cohort of 250 ALS-FTD patients, demonstrating that diagnostic phenotype, disease duration, and global cognition scores were the strongest predictors of non-motor and neuropsychiatric impairments. Separately, disordered sleep and disrupted mood were also commonly found in pure motor phenotypes, thus suggesting a shared underlying pathophysiology involving the entire phenotypic spectrum.Amongst the non-motor features of ALS, neuropsychiatric features have been less studied compared to cognitive dysfunction, especially in analyzing their frequency across the ALS-FTD spectrum of conditions. In their work on factors influencing non-motor impairment across the ALS-FTD spectrum, Pain et al., based on a cohort of Italian patients, demonstrated the validity, reliability, and clinical utility of the ALS Depression Inventory-12 (ADI-12) questionnaire to assess depression, independent of motor disability and separately from cognitive features such as apathy. ALS-specific, motor-independent tools are required for the screening of depression to distinguish between treatable reactive/psychogenic forms and non-treatable conditions related to motor and cognitive dysfunction in patients with ALS-FTD spectrum disorders. Although therapeutic approaches to mood disorders are well-known, interventions for cognitive and behavioral symptoms as part of ALS care remain poorly defined and adopted. The first step to develop successful neuropsychological management is to focus on the presence of illness perceptions among patients and caregivers. To this effect, Caga et al., using the Brief Illness Perception Questionnaire (BIPQ), showed that a greater perceived cognitive and emotional impact on ALS increased the risk of behavioral changes and was also associated with more rapid disease progression, underscoring the importance of tailored emotional support as part of multidisciplinary ALS care.Among the behavioral symptoms, apathy is the most frequently reported (detected in up to 70% of patients), although often concomitant and confused with depressed mood . Pain etTu et al. study confirmed a higher prevalence of pseudobulbar signs in bulbar onset ALS patients, applying the Center for Neurologic Study-Liability Scale (CNS-LS) as a validated tool. Using neuropsychological evaluation and magnetic resonance imaging (MRI), the authors also noted that pathological laughter correlated with executive dysfunction, brainstem volume reduction, and a lower fractional anisotropy of the superior cerebellar peduncles. Indeed, emotional lability could be underpinned by degeneration across distinct neural circuits with a critical role involving the brainstem.Among symptoms described by patients as most socially embarrassing are episodes of involuntary laughter or crying (pseudobulbar affect). On this aspect, McKenna et al.'s review focused on insights gained from structural, metabolic, and functional neuroimaging studies that have improved the understanding of extra-motor disease burden in ALS phenotypes that were less frequently associated with dementia, i.e., primary lateral sclerosis, progressive muscular atrophy, or post poliomyelitis syndrome. The paper confirmed the heterogeneity of extra-motor pathology across the spectrum of motor neuron disease and highlights the role of neuroimaging in characterizing anatomical patterns observed in cognitive impairment and neurodegeneration in vivo.Over the last several years, the acknowledgment of frontotemporal involvement in ALS has resulted in the extensive application of novel neuroimaging techniques . McKennaPaoletti et al. Their preliminary data showed that muscle damage in ALS is characterized by different MRI features in different phases of disease.Among neuroimaging tools, brain MRI has been commonly employed to monitor ALS disease progression . AnotherReyes-Leiva et al. reviewed the literature determining the role of different biomarkers of extra-motor neurodegeneration in ALS and their capability in identifying key pathophysiological changes at diagnosis (diagnostic biomarkers), to predict the risk or speed of progression (prognostic biomarkers), and to monitor response to therapy (therapeutic biomarkers) to characterize relevant aspects of disease pathophysiology . Considering the possible difference in pathological mechanism underlying cognitive and behavioral features in ALS-FTD spectrum conditions, the availability of various bodily tissue/fluid, neuroimaging, and neurophysiological and genetic biomarkers would improve the recognition in vivo of different degrees of neurodegenerative and neuroinflammatory changes thereby allowing the development of targeted molecular treatment (Although MRI can also be used in longitudinal studies, its utility to predict progression of disease has not been well-characterized, and is partly attributable to the lack of valid biomarkers in motor neuron disease. In this regard, reatment .In conclusion, the present Frontier Research Topic delves into the extramotor features in motor neuron disease, expanding the traditional perspective of a pure neuromuscular disorder to a more complex motor and cognitive spectrum. The study of pathophysiological mechanisms and phenotype characterization in ALS-FTD will ultimately improve diagnosis, staging and management, thereby facilitating the design of personalized symptomatic treatment that include psychological support, as well as more comprehensive design of clinical trials.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.WH was supported by the Lenity Foundation Fellowship, University of Sydney.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Fluoride is commonly found in the soil and water environment and may act as chronic poison. A large amount of fluoride deposition causes serious harm to the ecological environment and human health. Mitochondrial dysfunction is a shared feature of fluorosis, and numerous studies reported this phenomenon in different model systems. More and more evidence shows that the functions of mitochondria play an extremely influential role in the organs and tissues after fluorosis. Fluoride invades into cells and mainly damages mitochondria, resulting in decreased activity of mitochondrial related enzymes, weakening of protein expression, damage of respiratory chain, excessive fission, disturbance of fusion, disorder of calcium regulation, resulting in the decrease of intracellular ATP and the accumulation of Reactive oxygen species. At the same time, the decrease of mitochondrial membrane potential leads to the release of Cyt c, causing a series of caspase cascade reactions and resulting in apoptosis. This article mainly reviews the mechanism of cytotoxicity related to mitochondrial dysfunction after fluorosis. A series of mitochondrial dysfunction caused by fluorosis, such as mitochondrial dynamics, mitochondrial Reactive oxygen species, mitochondrial fission, mitochondrial respiratory chain, mitochondrial autophagy apoptosis, mitochondrial fusion disturbance, mitochondrial calcium regulation are emphasized, and the mechanism of the effect of fluoride on cytotoxicity related to mitochondrial dysfunction are further explored. Fluoride is abundantly existing in our environment in different forms and it can cause serious harm to the ecological environment and human health. Worldwide numerous cases of fluorosis have been observed. Especially, in China, the fluorine pollution in soil is of serious concern, as it is causing a greater negative impact on human health and ecological environment . The sitFluoride is a necessary element in the normal development and growth of animals, but excessive fluoride will cause damage to the animal body. A large number of phenomena showed that the typical manifestations of fluorosis are; dental fluorosis , hyperte+), the release of protons, leading to intracellular acidification, leading to oxidative stress  is the main mediator of Ca flowing into mitochondria, manipulating cell energy metabolism. ROS production and programmed cell death, all of which are essential for fluorosis  and effectors (Caspase 7 and Caspase 3) to induce apoptosis (2+ level is effectively transmitted to mitochondria by pro-apoptotic BCL-2 family proteins (Bax and Bak), and indirectly acts as an important upstream signal of apoptosis. The increase of mitochondrial calcium level stimulated the release of pro-apoptotic molecules such as CtyC. In addition, CtyC and APAF-1 formed apoptosis bodies and treated pro-Caspase 9, which led to the division of downstream Caspase 3 and Caspase 7 in the cytoplasm and endoplasmic lumen , the key R&D plan of Bayi District, Nyingchi City (2021-GX-SY-01), and the basic research funds of China Agricultural University (2021TC002).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Periodontal disease (PD) is an immuno-inflammatory condition, which is induced by the bacterial biofilm aggregates on external tooth surfaces. The condition affects and destroys the gingival tissue, periodontal ligament, cementum, and alveolar bone. Furthermore, in an indirect manner, the microorganisms can induce the host cells to express certain genes and release mediators, resulting in the exacerbation of the inflammatory response. The severity of PD is determined by the extent of tissue destruction caused by the immune response mounted by the host, probably influenced by environmental, acquired, or genetic risk factors.Periodontopathogenic bacteria are the primary causative agents to destroy the supporting periodontal tissues directly through the action of their components, particularly the lipopolysaccharides (LPS) on the cell wall of gram-negative bacteria and in secreted molecules. Although SRP is the standard procedure for periodontal treatment, it might fail in eliminating bacteria or modulating the host response.Treatment of PD should, therefore, involve the removal of dental biofilm and control of inflammation through scaling and root planing (SRP) as the conventional and essential procedures in periodontal therapy. (ACS) might be a promising material.In recent years, a variety of new techniques and materials have been introduced to help regenerate periodontal tissues, and autologous conditioned serumPeriodontal therapy aims to regenerate periodontal tissues. However, current treatments, including surgery, use of membranes to facilitate periodontal tissue maturation, and application of enamel matrix derivatives, have limited indications and outcomes, prompting researchers to develop novel strategies for tissue engineering purposes. Several cytokines have been reported to play crucial roles in the destruction of periodontal tissues. However, their role in each phase of the periodontal wound healing process is yet to be clarified. A new horizon in tissue engineering processes of periodontal structures might involve efforts to control and modulate the inflammatory response of the host to affect the secretion of cytokines or activate/inhibit them in a time‐dependent and site-specific manner. induced a dramatic and steep increase in the secretion of various anti-inflammatory cytokines (such as IL-1Ra) by exposing blood to glass beads. Such an observation laid the foundation for the production of ACS to be injected into intra-articular spaces in six sessions twice weekly for three weeks. This treatment modality is offered to human subjects in some European countries, and its application is even more widespread for equine OA since ACS significantly improves clinical lameness in horses, protecting cartilage against degradation.ACS, as a new therapeutic agent, was introduced in the mid-1990s in the form of an injectable agent rich in endogenous IL-1Ra for osteoarthritis (OA). Meijer et alIt seems the use of this material would be useful in procedures to regenerate periodontal tissues and treat periodontitis and peri-implantitis.