Currently, no single HIV prevention method meets the needs of all people at risk of infection and a range of options are needed for individuals to protect themselves and to curb the HIV epidemic. Many people living with HIV or at risk for HIV infection in low and middle-income countries do not have access to prevention, treatment and care, and there is still no cure. Despite large preventive efforts, HIV acquisition rates remain unacceptably high and transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Widespread violence, many sociocultural and economic factors in these regions limit the ability of women to insist on safer sexual practices to decrease HIV transmission risks. The development of vaginal HIV microbicides, the use of which would be discretely controlled or initiated by women, has therefore attracted much interest as a strategy to help prevent HIV sexual transmission. In this commentary, we discuss the evolution of vaginal microbicies, the different types that have undergone clinical trials, the past challenges to future hopes, the products that are currently in use and implications for women who are at risk to HIV infection in sub-Saharan Africa. Globally, there have been advances in the scientific understanding of HIV, its prevention and treatment, as well as years of significant effort by the global health community and leading government and civil society organizations. Due to the numerous antiretroviral (ART) drugs with different mechanisms of action currently available for treatment of HIV, the goal of ending the AIDS epidemic has become attainable through elimination of HIV and AIDS-related deaths in most parts of the world. In the past decade, new global efforts have seen the development and scaling up of highly effective and safe prevention tools, most notably using ART medications as both pre-exposure prophylaxis (PrEP) by uninfected persons to prevent HIV acquisition and as treatment for persons living with HIV to eliminate infectiousness . Both anDespite this progress, many people living with HIV or at risk of HIV acquisition, particularly in low and middle-income countries (LMICs), still do not have access to prevention, care, and treatment. Adolescent girls and young women aged 15-24 account for approximately 5000 new infections each week globally, with most in sub-Saharan Africa (SSA). SSA is home to two-thirds (67%) of people living with HIV and women in some African settings continue to bear a disproportionate burden of the global HIV-1 epidemic. Recent evidence has demonstrated that HIV incidence in young African women in some settings has seen no substantial decline over the past decade. Other than biological factors, the high risk of HIV infection among adolescent girls and young women in these regions is further amplified by widespread sexual violence, stigma, discrimination, poverty and gender equity factors. Furthermore, it is important to note that many LMICs hardest hit by HIV also face serious challenges due to other infectious diseases, food insecurity, additional global health and development problems thus hindering HIV prevention access . Thus, nThe development of vaginal HIV microbicides, self-administered prophylactic agents applied to the vagina, the use of which would be controlled by women as a strategy to prevent new HIV sexual transmission infections emerged nearly three decades ago. The successful development of these agents for the prevention of HIV infection requires significant levels of protection against HIV acquisition, demonstrated safety in healthy populations, and no adverse interactions with commonly used vaginal drugs or other HIV prevention approaches. The initial trend in the pursuit of an effective microbicide involved the use of non-HIV-specific substances to prevent the entry of the virus in order to block the first step of infection. For nearly two decades, the first-generation microbicides tested for efficacy, mostly in SSA, were formulated as gels without direct antiviral activity against HIV and included detergents; nonoxynol-9 (N-9) and C31G 9 (SAVVY), polyanions; Carraguard, PRO 2000 and cellulose sulphate (CS) and a vaginal acidifier BufferGel. While initially the early-phase clinical studies of these microbicides were promising, the results of larger trials failed to demonstrate efficacy . SuggestAfter unsuccessfully evaluating numerous compounds in clinical trials, the focus has switched to the study of potential microbicides with antiretroviral drugs that prevent virus replication. The first antiretroviral product evaluated was a gel containing 1% tenofovir (TNF), a nucleoside reverse-transcriptase inhibitor (NRTI) which acts in the case of HIV infection by blocking the activity of reverse transcriptase and preventing the virus from infecting cells and replicating. In 2010, a proof-of-concept for human HIV prevention by antiretroviral-based vaginal microbicides (ARV-VMB) was achieved in one clinical trial, the CAPRISA 004 study, in South African women. The 1% TNF gel was found to reduce HIV infection rate by 39% in women using the gel up to 12 hours before sex and again within 12 hours after sex, compared with women using a placebo gel . PartialThe reduction in HIV infection in women demonstrated by pericoital use of TNF gel in 2010 encouraged the continued development of antiretroviral microbicides. It established that effectiveness depends on consistent and timely use; therefore, design of formulations that women can routinely use with ease is of paramount importance in microbicide development. As a result, attention has shifted toward development of alternative formulations that require less commitment from the user to show efficacy, such as sustained release drug formulations ,8. WhileThe development of an effective microbicide for HIV prevention involves the selection of potent drugs that can interfere with HIV replication and deliver the drug to the site of replication at the appropriate time. Thus, both the drug and the drug-delivery system are crucial components of a successful product. Since consistent and correct use of the products are critical to their effectiveness, the active pharmaceutical ingredients must be delivered in acceptable vaginal dosage forms. The physical and chemical properties of antiretroviral-based compounds allow for their delivery in formulations designed for flexible dosing. The monthly DPV-VR is one such technology ,8. Previin-situ and side effects, as well as concerns about the ring interfering with sex and/or being noticed by the sexual partner. However, with use and increased familiarity, participants are reported to have appreciated the ring, found it easy to use and integrate into their lives and favored it over other delivery forms such as daily oral pills, condoms or gels. Interventions that include counseling and social support to improve adherence and retention have been carried out. Additionally, the dynamics of participants´ relationships with their male partners have been reported as the most consistently described drivers of ring acceptability and use, with consideration of male partners´ attitudes towards the ring identified as a theme across participant narratives [Multiple clinical trials have evaluated the acceptability of the DPV-VR among reproductive-age women in Africa. In these trials, women reported initial fears about the ring´s unfamiliar appearance, placement rratives . The iniTwo recent randomised, double-blind, placebo-controlled, phase 3 clinical trials have shown that a 25 mg DPV-VR ring used for 28 days is well tolerated with a favorable safety profile and demonstrated a modest but statistically significant reduction of approximately 30% in HIV acquisition by women ,7,8. TheThe creation of an effective microbicide also requires understanding the dynamics of the target population, and transmission prevention strategies must be adapted accordingly. Much of the current effort focuses on understanding the aspects that govern the effectiveness of microbicides, and adherence is a key consideration in the trials. Improving adherence ranges by supporting the users, assessing their perception of risk and analyzing their social background and relationship challenges, including whether their partners allow them to use microbicides. Among the key factors women consider when choosing a vaginally inserted product, whether for HIV prevention or other purposes, is its impact on sexual experiences for themselves and their partners. Ease of use, potential for longer acting protection and discreet use independent of coitus have made rings a focus for development of HIV prevention intervention delivery. It is noteworthy that as with any other interventions in existence, the effectiveness of rings as prevention products is positively correlated with adherence, which is likely to depend on user acceptability of the product. As mentioned earlier, the DPV-VR containing 25 mg DPV was found to be a safe and effective female-controlled method of HIV prevention ,7,8, marOne of its potential advantages over coitally dependent or daily use products is that it is longer-acting and just requires the user to leave the product in place over the course of the month to be adherent. Following the success of the DPV-VR, two open-label expanded trials among women who were HIV-1-negative who had previously participated in two phase 3 trials, have shown that use of the DPV-VR under conditions approaching real-world scenarios such as visits once every 3 months and less frequent HIV testing is acceptable and results in a reduction in the risk of HIV-1 seroconversion . The finThough most microbicide research has been undertaken in SSA and Southeast Asia, an effective microbicide will undoubtedly be used worldwide to prevent the sexual acquisition and/or transmission of HIV. Given social, demographic and migratory trends, the population at risk for STIs will continue to grow dramatically. The burden is greatest in SSA, but industrialized nations can also be expected to experience an increased burden of disease because of the prevalence of non-curable viral infections, trends in sexual behavior and increased travel. Based on a systematic review and meta-analysis of available scientific evidence on the long acting, sustained-release anti-HIV microbicidal product, the benefits outweigh the harms. This evidence includes the cost-effectiveness of the DPV-VR, acceptability, demonstrated feasibility, and the potential to increase equity as an additional prevention choice. Limitations of the data include the observed variability in effectiveness in younger age groups that need confirmation in further trials, and the limited data regarding the use of DPV-VR among pregnant and breastfeeding women.In conclusion, the HIV epidemic not only affects the health of individuals, it also impacts households, communities, and the development and economic growth of nations. With inequalities, power imbalances, violence, marginalization, taboos, stigma and discrimination in LMIC, particularly in SSA, HIV takes hold, and the war against HIV is yet to be worn in some settings in this region . Followi


The hedgehog (HH) family of secreted proteins, and the signaling pathway they trigger, play crucial roles in cell proliferation, differentiation and migration, not only in development, but also in many types of cancers. It is thus not surprising that it has been the focus of intense investigation by biochemists, geneticists and clinical doctors. Four decades of studies have revealed many levels of regulation, from the production, modification, release and degradation of the ligands, to the roles of various receptors, coreceptors, downstream kinases, phosphatases, and effector transcription factors. Strikingly, HH signaling in vertebrates has been associated with the primary cilium, a unique cell surface organelle whose critical roles in development and diseases were only appreciated in the past two decades. The importance of this pathway is further exemplified by the FDA approval of HH/SMOOTHENED (SMO)-blockers as a stand-alone anti-cancer therapy. To date, novel regulators and effectors of HH signaling continue to be identified, adding to the complexity of the molecular interaction network.The seven articles in this Research Topic reflect on the recent advances and provide perspectives in the molecular mechanisms of HH pathway regulation, the crucial roles of HH signaling in development and pathology, as well as new strategies for treating HH signaling related diseases including cancers.Nguyen et al. provide an overview on ciliary lipid compositions and their impact on HH signaling throughout evolution . In addition to ciliary membrane-specific phosphoinositides, this signaling pathway is stunningly dependent on many other lipids and sterols, functionally affecting HH ligand transport as well as intracellular signal transduction—a truly unique feature of the HH pathway.Given its significance for correct embryonic development and its involvement in the patterning of various tissues and organs, HH signaling is subject to tight regulation. One such layer of regulation is imposed by distinct lipid compositions specifying selected membrane regions as found in the primary cilium of vertebrates. Drosophila and mammals. Jia and Jiang outline the regulation of SMO trafficking by these post-translational modifications and hereby compare mechanistic concepts which arose in flies and humans (Jia and Jiang).One example for the intricate relationship between lipids and signaling is the SMO protein, which can be covalently and non-covalently associated with sterols. However, SMO is also subject to ubiquitination and SUMOylation, both of which constitute evolutionarily conserved control mechanisms of HH signaling in Zhou and Jiang provide a review on phosphorylation as a major mechanism of GLI regulation (Zhou and Jiang). They introduce our current understanding of cAMP-dependent protein kinase (PKA), Casein kinase 1 (CK1) and Glycogen synthase kinase 3 (GSK3)-mediated phosphorylation in the processing and activation of GLI proteins in vertebrates and invertebrates. They also discuss the latest research findings, some of which are still being debated, e.g., on the roles and regulations of ciliary cAMP in HH signaling. They also discuss the discovery of new GLI regulators, such as the Fused family of kinases, Polo-like kinase 1 (PLK1) and CK2, which catalyze the phosphorylation of GLI proteins, and contribute to their functional regulation.The Glioma associated oncoprotein (GLI) family of transcription factors are the effectors of the HH pathway, converting the HH signal into transcriptional responses leading to cellular outputs. He et al. report a study carried out in Drosophila, in which they generated a transgenic toolbox of in vivo miRNA sensors for the core components of the HH pathway, and performed a genome-wide in vivo miRNA overexpression screen in the developing wing imaginal disc . Out of 12 miRNAs identified through this screening, they report that miR-10 and miR-958 attenuate HH signaling by directly targeting fu and smo, respectively. The functional relevance of the newly discovered miRNAs was validated by overexpression experiments that altered HH’s role in cell fate specification during testis development.Micro RNA (miRNA) regulation of HH signaling has been an intense ResearchTopic over the past decade; however, the preferred genetic loss of function approach often yields dismally little useful information, possibly due to functional redundancy and contextual dependence of this class of regulators as a whole or each miRNA in particular. Here, Wang et al. review the roles of HH signaling in cerebellar development and cancer . They review classical genetic loss-of-function studies establishing SHH-mediated interaction between Purkinje cells (PC) and granule cell progenitors (GCP), two major neuronal cell types of the cerebellum. They focus on GLI targets that directly regulate cell proliferation, including Cyclin D (CycD), Cyclin-dependent kinase 4 (Cdk4), MYCN, and their roles in the pathogenesis of medulloblastoma (MB), a pediatric cerebellar tumor. Finally, they discuss the use of inhibitors for SMO, GLI and downstream CDKs as therapeutic strategies for MBs. Some of the inhibitors are already approved or in clinical trials for MB treatment, attesting to the clinical importance of understanding the roles of HH signaling in cerebellar development and MB etiology.HH signaling plays essential roles in the development of many organs, and when abnormally activated, leads to malignancies. Tesanovic et al. present another example of the importance for well-orchestrated HH signaling in normal developmental processes, and how its dysregulation leads to malignancies such as acute myeloid leukemia (AML), one of the most lethal types of blood-borne cancers . HH signaling is critical for the persistence of therapy-refractory leukemic stem cell pools and a SMO inhibitor has recently been approved for clinical use in AML, significantly expanding the application repertoire of this class of compounds beyond that of basal cell carcinoma.Ma et al. studied the roles of parathyroid hormone (PTH) in fracture healing using a mouse model . They show that endogenous PTH is required for efficient fracture healing, and a shortened exogenous PTH fragment (PTH 1–34) can rescue the fracture healing defects in Pth mutant mice. Importantly, they find that PTH 1–34 promotes cAMP response element binding protein (CREB) phosphorylation and subsequent activation of Ihh expression. This work suggests that PTH 1–34 can be an effective treatment for fracture, and points to an important role of IHH signaling as the underlying mechanism.Another HH family member, Indian hedgehog (IHH), plays a critical role in chondrogenesis in development. In summary, the seven articles, authored by experts at the forefront of the HH signaling field, cover a wide range of research areas, from basic mechanisms of HH signal transduction and pathway regulation, to the connection between HH signaling and various diseases. Finally, current and potential treatments of various cancers as well as of bone fracture repair are presented. Hence this Research Topic provides a timely update on the latest progress in the study of HH signaling in development and disease, and points out pressing questions and future directions.


The global incidence and prevalence of facial fractures rose by 39.45% and 54.39%, respectively, between the years 1990 to 2017. Projections indicate that the burden of injuries will persist in sub-Saharan Africa (SSA) in the next twenty years. This scoping review aims to map the literature on MI epidemiology and the economic burden on society in SSA. (2) Methods: The methodology presented by Arksey and O’Malley and extended by Levac and colleagues will be employed in the scoping review. The researcher will report the proposed review through the Preferred Reporting Items for Systematic Review, and Meta-Analysis extension for scoping reviews (PRISMA-ScR). The review will include studies encompassing MI in sub-Saharan African adults 18 years and above. (3) Results: This will be presented as a thematic analysis of the data extracted from the included studies, and the Nvivo version 12 will be employed. (4) Discussion: We anticipate searching for related literature on the prevalence, incidence, risk factors, mortality, and cost associated with MI in the adult population of SSA. The conclusion from the review will assist in ascertaining research gaps, informing policy, planning, authorizing upcoming research, and prioritizing funding for injury prevention and management. Evidence has shown that injuries account for a significant health burden in many countries annually ,2,3. TheStudies have identified the commonest mechanisms of injury in the maxillofacial region as; motor vehicle and motorcycle collisions ,13,14, aThe higher ratio of injury YLDs in LMICs is yet to be translated to the investigations of the health burden associated with this nature of injury . This diA scoping review systematically maps the literature on a topic by identifying key concepts, theories, and sources of evidence that inform practice in the field. Therefore, this projected scoping review will employ the available literature (peer-reviewed and grey) on the distribution of maxillofacial injury involving adults in SSA underpinning, prevalence, incidence, risk factors, mortality, and the economic burden. This review forms part of the main research study, which aims to define the burden of maxillofacial injury among adults in Lesotho. The database search and screening outcomes from diverse studies will be reported using the PRISMA flow diagram. The proposed scoping review will be reported by applying the guidelines for observational studies in epidemiology and the preferred reporting items for systematic reviews and meta-analysis extended for scoping reviews (PRISMA-ScR) checklist and explanation . The metStep 1: To identify the research questions.The principal research question of the scoping review is as follows:What is the prevailing evidence on the distribution of maxillofacial injury among adults in SSA?Sub-questions(a)What is the burden of maxillofacial injury in SSA with estimations on the prevalence, incidence and mortality?(b)What risk factors are associated with maxillofacial injury in SSA?(c)What are the estimated costs associated with maxillofacial injury?The eligibility of the research question for this proposed scoping review will be determined using the; population, concept, and context (PCC) framework , as demoStep 2: Identification of relevant studiesSources of informationThe authors will conduct the keyword search of literature in English. In the proposed review, identifying the studies of relevance will be guided by the inclusion and exclusion criteria, which will be carried out without a date limit. The author will perform an electronic literature search through the following databases: Google Scholar, Web of Science, Medline, EBSCOhost, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Health Source: Nursing/Academic Edition, PubMed, Embase, Emcare, and Scopus. Furthermore, we will search for grey literature from institutional repositories, government and international organisations’ reports such as the WHO and from university dissertations and theses. Foremost to be employed in the study will be a comprehensive search approach that considers the keywords, medical subject headings (MeSH), or subject headings search terms that relate to key concepts, as well as Boolean terms “AND” and “OR”. The keyword terms to be used for the literature search will include; maxillofacial trauma, maxillofacial injury, facial trauma, facial injury, facial bone trauma, facial bone injury, facial lacerations, mandibular fracture, mandibular trauma, mandibular injury, maxillary fracture, maxillary injury, nasal fracture, nasal injury, orbital fracture, orbital injury, epidemiology, prevalence, incidence, risk factors, disability, mortality, burden, comorbidities, associated cost and countries in Sub-Saharan Africa. The piloted search strategy in PubMed is demonstrated in Table . FurtherStep 3: Study selection and inclusion criteriaEligibility criteriaInclusion criteriaThe prevalence of maxillofacial injury in SSAThe incidence of maxillofacial injury in SSAThe risk factors associated with maxillofacial injury in SSAThe comorbidities associated the maxillofacial injuryStudies that have a clear definition of maxillofacial injuryThis proposed review will include all studies conducted among the adult population aged 18 years and above that present evidence on any of the factors listed below:Exclusion criteriaEvident articles involving individuals under the age of 18 yearsReview studiesStudies conducted outside the setting of SSAClinical trials and intervention-based studiesStudies carried out in other languages other than English and do not have an English versionStudies that lack a clear definition of maxillofacial injuryThis review will exclude the following:Selection ProcessThe screening process of articles will be carried out in three stages, namely, title, abstract and full article screening. The principal investigator (PI) will conduct the title screening. In contrast, the abstract and the full article screening will be autonomously carried out by the PI and the co-reviewer (CR). A comprehensive title screening will be conducted in the electronic databases described by the PI, with the assistance of the Institution (UKZN) librarian. Articles found eligible at the title screening stage will be exported to an Endnote version 20 library, where duplicates will be detached. Two independent reviewers, the PI and CR, will co-screen articles for valuation against the inclusion criteria, and studies that meet the inclusion criteria will be incorporated for the next phase of abstract screening. This stage will be followed by full article screening, independently conducted by the PI and CR. These two (PI and CR) will appraise the selected articles following the inclusion criteria. In the case of any discrepancy in a selected article at both stages (abstract and full article) between the PI and CR, clarifications and discussions will be held to obtain a consensus. The failure to obtain a consensus between the PI and CR will result in the help of a third screener for resolution. The EndNote library “Find full text” option will be applied to download PDFs of exported studies spontaneously. The assistance of the Institution librarian will once more be sought at the full article stage on acquiring articles that cannot be fully accessed freely. Furthermore, the assistance of corresponding authors will be sought through email to request a full-text article, if essential. The level of agreement between screeners’ (interrater) results after screening for abstracts and full articles shall be determined through the application of Cohen’s kappa statistic on reliability . The intStep 4: To chart the data.The PI will employ the Google form for this process by developing a data charting (extraction) form. After thoroughly reading the full text, the PI will use the form to extract information from each relevant study. The pilot study of this process (data charting) will be conducted to guarantee its accuracy and carried out by the reviewers before the scoping review. The feedback received from this process will guide the modification of the data form. This process will be regularly updated during the entire period of the scoping review to allow the capturing of all pertinent data applicable to answer the research question. The details to be captured by the data form will include; (i) Author and date of publication, (ii) Study setting, (iii) Publication type, (iv) study design (sample size), (v) Peak age range of incidence, (vi) Male/Female ratio, (vii) Major cause of Maxillofacial injury, (viii) the second major cause of Maxillofacial injury, (ix) Maxillofacial soft tissue affected, (x) cost of management, (xi) other relevant findings to answer the research question, and (xii) conclusion.Step 5: To collate, summarize and report the results.This stage will encompass the thematic analysis of the extracted data, for reporting and making sense of the results. The extracted data from the included articles will be descriptively summarized and exposed to a thematic analysis by employing Nvivo version 12. The presentation will assume the narrative of the appropriate themes and sub-themes along with the research questions as the; (i) prevalence, incidence and mortality, (ii) risk factors, and (iii) associated costs. The use of tables and figures will be employed in the result presentation when necessary.Step 6: Methodological quality appraisalThe quality of the methodological method employed will be determined by applying the mixed methods appraisal tool (MMAT) . Two indEthical approval and consent to participateThis review will be exempted from ethical approval, for it is based on data reported in publicly accessible databases and publications.Potential limitations to the scoping reviewThere is a paucity of literature on the epidemiology and the associated economic burden of maxillofacial injury in SSA. Hence, this may result in limited literature for the scoping review. Furthermore, there is the potential to miss relevant articles given that articles published in English will only be considered for the review.The proposed scoping review aims to map the available evidence regarding the epidemiology, risk factors, and estimated costs associated with maxillofacial injury among adults in sub-Saharan Africa. The review is expected to highlight the under-explored areas in this injury. This scoping review will comprise observational studies and cost of management study designs carried out among adults in SSA. All relevant studies in English, and without date limitations will be included. To be excluded from the review will be randomized controlled clinical trials and intervention-based studies. This is because the data from such methodologies will not be appropriate for addressing the research question of the coping review. The review is a pioneer study to map the evidence on the distribution of MI in SSA, with appraisals on prevalence, incidence, mortality, risk factors, and associated cost. The National Trauma Data Bank report revealed that approximately 25% of all recorded injuries involve the face . The facThe sustainable development goal (SDG) 3 targets ensuring healthy lives and promoting well-being for all ages . Hence, The outcomes from this projected scoping review are anticipated to give a projection on the distribution of MI in SSA with appraisals on prevalence, incidence, risk factors, mortality, and associated economic burden. Hence, the synthesized evidence from the study will help researchers, decision-makers, and other stakeholders to inform policy and ensure an effective allocation of healthcare funding. Furthermore, this will help in upgrading the healthcare system performance and thus improve measures on injury prevention and the interventional process.


Background: The World Health Organization identified alcohol and tobacco consumption as the risk factors with a greater attributable burden and number of deaths related to non-communicable diseases. A promising technique aimed to modify behavioral risk factors by redesigning the elements influencing the choice of people is nudging. Methodology: A scoping review of the literature was performed to map the literature evidence investigating the use of nudging for tobacco and alcohol consumption prevention and/or control in adults. Results: A total of 20 studies were included. The identified nudging categories were increasing salience of information or incentives (IS), default choices (DF), and providing feedback (PF). Almost three-quarters of the studies implementing IS and half of those implementing PF reported a success. Three-quarters of the studies using IS in conjunction with other interventions reported a success whereas more than half of the those with IS alone reported a success. The PF strategy performed better in multi-component interventions targeting alcohol consumption. Only one DF mono-component study addressing alcohol consumption reported a success. Conclusions: To achieve a higher impact, nudging should be integrated into comprehensive prevention policy frameworks, with dedicated education sessions for health professionals. In conclusion, nudge strategies for tobacco and alcohol consumption prevention in adults show promising results. Further research is needed to investigate the use of nudge strategies in socio-economically diverse groups and in young populations. Tackling the burden of non-communicable diseases (NCDs) is a key public health goal . In thisIn order to target these modifiable risk factors, many health promotion interventions are possible ,11. In tNudge: Improving Decisions about Health, Wealth, and Happiness [Among these interventions, a promising and emerging technique in this regard consists in nudging. Thaler and Sunstein, in their groundbreaking work appiness , define appiness ,17,18,19Nudging theory, which emerged from the field of behavioral economics , was intInspired by behavioral economics, nudging techniques tap into cognitive biases and induce people to act and respect the interests and wellbeing of themselves and others . ExpertsNudging has been progressively applied to medicine  and publIn the public health context, nudging has been used to address individual choices to produce desired behavioral changes, with the aim of enhancing population health outcomes. In particular, as it directly influences the behavior of individuals whilst preserving autonomy , nudgingWith regard to the action upon the two aforementioned major chronic disease risk factors—alcohol and tobacco consumption—a recent systematic review by Blaga et al.  showed tFollowing the methodological framework proposed by Arksey and O’Malley  and refiThe eligibility criteria were defined according to the population, concept, and context (PCC) framework . ParticuGiven the nature of the intervention, the considered community settings were primary care clinics, community centers, and online platforms. The inclusion of studies was also restricted to the article type , language , and availability of full texts. Both the first round of screening by titles and abstracts and the second one by full texts were conducted by four independent authors. Any potential disagreements were resolved by a fifth researcher.An electronic data extraction form was set up to collect, for each included paper, information about the general characteristics of the study  as well as the population, setting, type of nudge-based intervention, and outcomes achieved. The data extraction process was carried out by four independent authors. The nudge-based interventions described by each included study were classified according to the categorization available in the seminal work by Thaler and Sunstein and already reported in the scientific literature . The refp-values and confidence intervals for the quantitative studies or the adopted conceptual frameworks for the qualitative studies.A preliminary descriptive synthesis was conducted tabulating a summary of the general characteristics of the included studies. Moreover, a narrative synthesis was performed considering several types of nudge-based interventions in healthcare for the prevention and/or management of tobacco and alcohol consumption and the relative observed success rate. The success rate was intended to describe the final outcome of the investigated intervention by analyzing either the reported Overall, after data de-duplication, the search strategy resulted in 3051 records from all the scientific databases. Of the total number, after the two rounds of screening , 3031 studies were screened out due to an incompatibility with the inclusion criteria . As a result, 20 studies ,60,61,62Of the 20 studies in the final review, 10 50%) % 50,53,,60,61,62,61,6260,Furthermore, seven (35%) studies ,54,57,61The use of several nudge types that were adopted in the included studies as interventions was assessed and classified according to the classification by Thaler and Sunstein as well as evidence available in the scientific literature.The present review showed that the retrieved articles on the prevention of alcohol and tobacco consumption examined the use of three out of six nudge strategies .Increasing salience of information or incentives (IS). The most popular nudge strategy adopted was IS, which aims to increase the salience of information or incentives to steer the attention of individuals to the desired choice. Fourteen of the included studies implemented the IS strategy. Of the fourteen studies, ten used IS alone  whereas the remaining four articles adopted the hitherto-cited choice architecture in combination with other interventions . Providing feedback (PF). According to the included evidence, the second nudge strategy adopted was PF, which implies the provision of information to individuals on the consequences of their behavior. Four of the included articles adopted the PF strategy. Out of the four studies, one-half used PF alone and the other half used a combination with other interventions. Default choices (DF). Default choices, the nudge strategy that puts the choice setting along the path of least resistance, was another strategy examined. Its adoption was investigated in two of the studies. Of the two studies, one used DF alone whilst the other used DF in conjunction with other interventions. Overall, of the fourteen studies using IS as choice architecture strategy either alone or in combination with other interventions, most reported a success; however, four out of fourteen reported a lack of success. When used in conjunction with other interventions , the IS strategy led to successful results in three studies, whereas, when taken alone , successful findings were reported in six studies.Of the four studies implementing PF as a nudge strategy, half described successful findings and the other half reported a lack of success. Particularly, when used in combination with other interventions, it seemed that the PF strategy performed better in preventing the risk factors associated with alcohol consumption with respect to using it as a stand-alone strategy, which, on the contrary, failed to achieve successful results for preventing the risk factors related to tobacco consumption.Only one study reported successful results addressing alcohol consumption adopting the DF nudge strategy alone. The other study, focusing on tobacco consumption and implementing DF jointly with additional interventions, failed to achieve significant findings.The present review found that the IS nudge strategy was the most adopted among the included articles. Furthermore, the review showed a higher overall success rate for the studies adopting the IS nudge strategy both for alcohol and tobacco consumption prevention.Framework Convention on Tobacco Control (WHO FCTC) for regulating the use of health-warning graphic labels depicting the health risks and potential health effects caused by smoking [Considering the nature of the IS choice architecture, the review results were endorsed by evidence in the scientific literature highlighting the larger effectiveness of image-based warning signs at communicating risk and discouraging dangerous activities . Particu smoking . For alc smoking ,68. As w smoking . This ca smoking .The underlying mechanism lies in negative emotional stimuli such as fear, disgust, discomfort, and worry, which are triggered by warnings . Other aStaying in the area of prevention, in addition to tobacco and alcohol, this type of intervention also appears to be effective in reducing sugary drink purchases, thus tackling the obesity burden . FurtherAccording to our findings, another frequent nudge was the PF type. We found that two out of the four studies deploying this type of nudge intervention achieved positive outcomes. The literature suggests that nudges on information and feedback might actually lead to weaker impacts, supposedly caused by distractions or information overload compared with more powerful tools . AttentiThe joint reading of the study findings led to a first main implication, which was the support in informing programs and policies for health prevention. Indeed, evidence-based nudges can be viewed as useful public health policy tools, despite the complex environment surrounding and affecting people’s health decisions . To ensuThe present study must be assessed considering its main limitations and strengths. First, a limited number of articles was included because most of the retrieved occurrences did not adopt nudge-based interventions. However, a robust process comprising the search strategy, study selection with strict inclusion criteria, and data synthesis was conducted to improve the study relevance. Moreover, there was heterogeneity among the nudge strategy categories identified based on several interventions. Nevertheless, the heterogeneity could be explained by the structural and methodological diversity among the included manuscripts. In addition, a quality assessment of each analyzed paper was not conducted; thus, a potential risk of bias was not considered. However, no formal quality assessment is required for scoping reviews . A notewFurther studies are required to evaluate nudge-based interventions for alcohol and tobacco consumption prevention by conducting, from a multi-dimensional and multi-professional perspective, tailored assessments for each domain  characterized by the Health Technology Assessment process . The durParticularly, investigating the equity dimension in applying nudge strategies to socio-economically diverse groups is of paramount importance for the development of tailored prevention campaigns. Moreover, additional research is required to assess nudge-based interventions for health prevention in young populations. Based on the available information, the present review documented a large dominance of IS and PF nudges applied to tobacco and alcohol consumption prevention in adults, with mixed results on their effectiveness.It is important to identify the specific outcome measures in a comprehensive prevention framework ,70 to peGiven the importance of the burden of disease generated by tobacco and alcohol, researchers, professionals, and stakeholders should consider and evaluate combined strategies and their benefits, and assess their impacts in the healthcare context.


While randomized controlled trials (RCTs) are the gold standard for evidence-based medicine, they do not always reflect the real condition of patients in the real-world setting, which limits their generalizability and external validity. Real-world evidence (RWE), generated during routine clinical practice, is increasingly important in determining external effectiveness of the tightly controlled conditions of RCTs and is well recognized as a valuable complement to RCTs by regulatory bodies currently. Since it could provide new ideas and methods for clinical efficacy and safety evaluation of traditional Chinese medicine (TCM) and high-quality evidence support, real-world study (RWS) has received great attention in the field of medicine, especially in the field of TCM. RWS has shown desirable adaptability in the clinical diagnosis and treatment practice of traditional Chinese medicine. Consequently, it is increasingly essential for physicians and researchers to understand how RWE can be used alongside clinical trial data on TCM. Here, we discuss what real-world study is and outline the benefits and limitations of real-world study. Furthermore, using examples from TCM treatment on cancer, including Chinese herbal medicine, acupuncture, moxibustion, integrated TCM and Western medicine treatment, and other treatments, we elaborate how RWE can be used to help inform treatment decisions when doctoring patients with cancer in the clinic. Real-world study refers to the process of the collection of data  related to the health of research subjects in a real-world setting or aggregated data derived from preset clinical questions and through analysis, to obtain medication utilization, potential benefits, and benefit-risk clinical evidence. Real-world data refer to diverse data collected on a routine basis related to physical conditions of patients besides diagnosis, treatment, and care. Not all real-world data can become real-world evidence after analysis, and only real-world data that satisfy applicability can generate real-world evidence. Real-world evidence refers to clinical evidence on the use and potential benefit-risk of a drug obtained through appropriate and adequate analysis of applicable real-world data, including evidence from retrospective or prospective observational studies or interventional studies such as pragmatic randomized controlled studies . RWS is For a long time, it has been firmly convinced that RCT is the most effective research mean to verify causality and the gold standard for testing treatment effects which drive the high internal authenticity and accuracy conclusions of research studies , 9, 10. Traditional clinical trials play a very vital role in promoting the modernization and standardization of traditional Chinese medicine, but traditional Chinese medicine emphasizes the integration of heaven and earth, respects individual differences, and follows the characteristics of syndrome differentiation for treatment, which determines that the types of studies mentioned above are difficult to reflect the curative effect and characteristic advantages. Based on real-world settings, which generalizes the conclusions, the emergence of RWS compensates for the insufficiency of RCT . TherefoClinical efficacy and safety have always been the core content of research in the field of traditional Chinese medicine. However, with the continuous deepening of research as well as its limitations, RCTs have been unable to meet the clinical demand of traditional Chinese medicine which is considered with unique diagnostic advantages. In recent years, how to scientifically and objectively evaluate the validity of traditional Chinese medicine in a real-world setting has become a hot topic in clinical research. As an important supplement to randomized controlled trials, real-world study is one of the approaches in line with the scientific research paradigm of TCM clinical research. Based on the characteristics of clinical diagnosis and treatment of traditional Chinese medicine, it collects a large amount of real-world data, as well as incorporates clinically meaningful outcomes, so as to mine and evaluate the efficacy and safety of traditional Chinese medicine in the real world.Traditional Chinese medicine has remarkable effects on cancers in the clinical practice, either directly inhibiting the occurrence and development of tumors, or reducing the side effects caused by chemotherapy and radiotherapy, or reducing the dosage of other therapies. Kuo conducted a real-world analysis of 582,799 adult cancer patients in Taiwan based on whether they used traditional Chinese medicine. The main analysis was the use of traditional Chinese medicine, as well as specific medical visits. After the adjustment of age, gender, urbanization of residence, occupation, annual medical center visit, and annual nonmedical center visit, adjusted hazard ratios (aHR) for mortality were significantly lower among TCM users than those who do not get TCM. This study indicates that more attention should be paid to the use of traditional Chinese medicine in the clinical diagnosis and treatment of cancer patients .Since acupuncture, moxibustion, and other treatments of TCM are rarely used in the treatment of tumors alone, they are mainly used to treat the adverse reactions and tumor-related complications. Therefore, this paper mainly focuses on the discussion of Chinese herbal medicine. Lung cancer is the most common malignant tumor of the respiratory system, accounting for most of the tumors of the respiratory tract . BuzhongThe most common tumors of the digestive system are colorectal cancer, pancreatic cancer, liver cancer, intrahepatic bile duct cancer, and gastric cancer . A totalBreast cancer (BC) is the second most commonly diagnosed cancer in women in the United States and a prime reason for death in women globally . A real-Chinese herbal medicine also plays a significant role in treating other cancers. As for cervical cancer, Bai-Hua-She-She-Cao  and Jia-Wei-Xiao-Yao-San were the most commonly used single-flavor Chinese medicine and Chinese herbal formula, respectively. After treatment, compared with cervical cancer patients who did not use Chinese herbal medicine, the survival rate of cervical cancer patients who took Chinese herbal medicine was significantly improved . One stuIn China, more than 4 million people are diagnosed with cancer every year, and with its morbidity and mortality, it ranks first in the world and has become a major public health problem that seriously endangers human health . ConventReal-world study has received global attention since its inception due to its consistency to clinical practice . China, Despite there are already reviews on the clinical efficacy and mechanism of TCM in the treatment of cancer, the clinical efficacy of TCM in the real world remains to be studied . In the All in all, the application of RWS in the field of traditional Chinese medicine has great potential in the future and will dispose of more problems closely related to clinical practice. We expect that better design and analysis methods can be discovered, adjusted, and applied, and the limitations and problems of the application of RWS can be better solved.


Owing to amplified impacts on human society and ecosystems, compound events (or extremes) have attracted ample attention in recent decades. China is particularly vulnerable to compound events due to the fast warming rate, dense populations, and fragile ecological environment. Recent studies have demonstrated tangible effects of climate change on compound events with mounting impacts on the economy, agriculture, public health, and infrastructure in China, posing unprecedented threats that are increasingly difficult to manage. Here, I synthesize recent progress in studies of compound events and associated impacts in China. Several lines of evidence indicate an increase in the frequency and intensity of multiple types of compound events across China. Future directions in studying compound events in China are suggested, including investigating extremes from a compound perspective, modeling compound events in the Anthropocene, quantitative evaluations of risks, and holistic adaptation measures of compound events.  Earth sciences; Integrated geography; Climatology; Hydrology China has been gripped not only by individual weather and climate extremes   but alsoA variety of compound events have been evaluated in China, including compound hot extremes, compound dry-hot extremes, compound wet-hot extremes, and compound flooding, as shown in Compound hot extremes are commonly defined as combined daytime-nighttime hot extremes . The dayCompound daytime-nighttime hot extremes have become more frequent and longer in China. Owing to the urban heat island (UHI) effect associated with increased urbanization , a largeProjections of compound hot extremes reveal an increase in the future, with a higher risk in urban areas . Under tThe concurrent or consecutive occurrences of droughts  and hot extremes are often termed compound dry-hot extremes . They may induce amplified impacts on agriculture, ecosystems, and water resources, which can be higher than that from individual droughts or hot extremes. Stationary anticyclones , land-atmosphere feedbacks (associated with soil moisture impacts on surface temperature), and large-scale modes of variability  can induce the negative dependence between droughts and hot extremes, resulting in the concurrence of the two extremes of different time scales . These dIn the past 60 years, an increase in the frequency, duration, and spatial extent of compound dry-hot extremes is observed in China, especially after the 1990s , which iCompound wet-hot extremes are usually defined as the consecutive or sequential occurrences of wet conditions  and hot extremes over a specified period. The combined impacts of high temperature and humidity on human discomfort or health have been well recognized . Owing tThe occurrence of hot extremes followed by heavy rainfall with some lags  is one type of compound events . The weather or climate conditions of heatwaves can favor the occurrence of heavy precipitation. Specifically, high surface temperature and sensible heat flux associated with heatwaves can enhance the convective available potential energy (CAPE) and provides favorable conditions for the development and maintenance of heavy precipitation , which, combined with alternatively anomalous anticyclones and cyclones , can produce the consecutive occurrences of heat and extreme precipitation . Since tThe sequential occurrences of flood events followed by heatwaves within a prescribed temporal interval  are a newly developed compound wet-hot event recently. Their underlying negative impacts result from the fact that after the blackout caused by flooding, a higher vulnerability of human health to following hot extremes can be induced, as witnessed during the sequential flood-heatwaves in July 2018 in Japan . In soutThese two types of compound wet-hot extremes are shown to increase in future periods. Projections from climate models indicate a significantly increasing trend in the frequency of compound heat-precipitation events by the end of the 21st century (increase by 1- to 5-times) over most regions of China . In addiFloods in coastal regions are related to the extreme sea level , river discharge, and surface rainfall-runoff  . CompounThe recent focus on compound weather and climate extremes has highlighted the need of viewing extremes through the lens of a compound perspective. A large number of compound events studies in China focus on temperature-related extremes . The important role of urbanization in affecting regional weather/climate extremes  and human-related factors  influence occurrences or impacts of compound events . The dirextremes  and landThe collation and synthesis in Section The lack of collaboration between disciplines and sectors  also hinders the risk assessments of compound events with influences on multiple sectors that are possibly interconnected. For example, it is challenging for regional climate, hydrology, agriculture, and socioeconomics systems to cover the entire chain of risk analysis , including hazards, exposure, vulnerability, impacts, or risks. Encouragingly, there are interdisciplinary research efforts that employ compound climatic hazards as drivers to perform quantitative risk analysis in other disciplines or communities. For example, the epidemiology community has used compound hot extremes as drivers to quantify mortality risk in China by incorporating the vulnerability of people of different age and gender groups . This caFrom the methodological perspective, certain new developments of model simulations and evaluations of compound events have not been widely employed for risk estimation of compound events in China. First, some compound events have an extremely low probability, which makes them difficult to sample and model based on observational records or historical simulations. In addition, compound events are subject to modulation of unforced internal variability, the realizations of which are under-sampled in the Coupled Model Intercomparison Project (CMIP) simulations . The sinWhether extremes lead to disasters will also depend on adaptation measures. Climate change and associated extremes have affected different aspects of the society in China  and multMeanwhile, there may be compounding consequences of adaptation options to compound risks. In other words, the human adaptation options or response of one risk may increase or decrease the risk of other extremes . For exaCompound events are related to the occurrences of multiple events (either the same or different variables) at certain temporal sequences  and/or spatial locations (either single or multiple) leading to impacts on different sectors of natural and human systems, where the compounding effects can be associated with the hazard, exposure, or vulnerability. These events have struck China with disastrous impacts on agriculture, water resources, human health, infrastructure, and ecosystems in recent decades. The past decade has witnessed increasing efforts in investigating diverse types of compound events, including compound hot extremes, compound dry-hot extremes, compound wet-hot extremes, and compound flooding, which covers a wide range of research topics, such as change detection and attribution of observed changes and projection of future changes. However, for different types of compound events in China, diagnosing physical processes of event occurrences, attributing their changes, quantifying risks, and developing adaptation measures are overall under-explored.Besides improvements in datasets and models for investigating compound events, several lines of effort are needed for future studies. A compound perspective on extremes  of different temporal and spatial scales is needed to further our understanding of recent extremes. In addition, the interaction of human activities  with the natural system in China should be considered in the modeling of compound events, which calls for the integration of physical drivers and societal drivers in understanding compound events. Moreover, the risk assessment of compound events should incorporate the dimension of exposure and vulnerability, especially in regions with large farm areas, fast urbanization, and dense and increasing population. This calls for enhanced cooperation between disciplines and sectors and updated methodology in estimating low-probability risk using large ensembles and evaluating model performance for simulating compound events. Last but not the least, the effectiveness of adaptation responses to multiple risks of compound events should be assessed by incorporating potentially compounding consequences of adaptation measures. As weather and climate extremes likely to increase with continued warming, further research on understanding and modeling compound events or extremes is essential to build resilience to climate change impacts in China.


One of the intriguing features of the mammalian olfactory system is the integration of newly generated sensory neurons and interneurons in the olfactory bulb throughout our life. The continuous reconstitution of the olfactory neural circuit that arises from the integration could modify the olfactory information processing, and thus impair the olfactory image of objects. Therefore, to maintain the olfactory perception, the olfactory system has developed homeostatic plasticity which works under physiological and even pathophysiological conditions.This Research Topic intends to represent the most recent and exciting results focused on understanding the mammalian olfactory system covering the olfactory epithelium to higher olfactory centers, from molecular mechanisms to olfactory recognition.We are truly thankful to all contributors to this Research Topic. Twenty-six authors contributed original research and review articles. Furthermore, we are deeply appreciative of all reviewers and editors who helped us to make an interesting, high-quality, and exciting Research Topic.Mori et al. examined whether the rat olfactory neuroepithelium fully recovers after the mucosal resection. Partial regeneration of the neuroepithelium was observed within 1 month after resection, whereas subsequent degeneration into squamous and respiratory epithelia occurred within 3 months. The authors conclude that, because of the poor neuroepithelial regeneration after the mucosal resection, surgeons should be cautious not to injure the olfactory mucosa during nasal surgery. Kikuta et al. examined the effects of insulin on the prevention of olfactotoxic drug-induced neuroepithelial injury in mice. Unilateral insulin administration prevented the methimazole-induced reduction in the number of olfactory sensory neurons on the ipsilateral side. Intranasal administration of eosinophilic cationic protein damaged the olfactory neuroepithelium by inducing apoptosis, but this damage was largely prevented by insulin administration. Therefore, insulin administration might lead to the development of new therapeutic agents for olfactory neuroepithelial injury. The information provided by these papers is valuable for our understanding of homeostasis of the olfactory neuroepithelium as well as for the development of a therapeutic strategy for olfactory dysfunction.In this section, two papers have described research data about the homeostasis of the olfactory neuroepithelium. Mori and Sakano summarize the recent progress in olfactory information processing during the respiratory cycle. The authors highlight studies suggesting that the tufted cell pathway associated with learned decisions is activated during the inhalation phase, while the mitral cell pathway is stimulated during the exhalation phase for instinct decisions. Furthermore, differential processing of orthonasal and retronasal signals in separate areas of the olfactory bulb and olfactory cortex is proposed in this review. Maegawa et al. report the expression of prodynorphin (Pdyn) and preproenkephalin (Penk), precursors of endogenous opioids, in the mouse olfactory tubercle. Using the multiple-fluorescence in situ hybridization technique, the authors show that Pdyn and Penk are primarily expressed by cells expressing dopamine receptors D1 (Drd1) and D2 (Drd2), respectively. Furthermore, it is shown that there are Pdyn-Penk-Drd1 co-expressing cells, which are found more abundantly in the anteromedial olfactory tubercle than in the anterolateral olfactory tubercle. These two articles provide important insights into olfactory circuitry and olfactory information processing.Two papers on neural circuits and information processing in the olfactory system have contributed to this Research Topic. Zhang et al. reported in this Research Topic that an unpleasant odor induced larger cue-related EEG responses in the alerting and executive control networks which correlated with a reduced behavioral response time of cue-related trials. Interestingly, these responses were irrespective of the odor concentration. These findings support ecological evidence for unpleasant odors acting as warning signals to help humans to stay alert to potential threats in the environment. The findings also provide cognitive performance evidence to support the relevant arguments of evolutionary psychology as well as situations in real-world daily life.The olfactory system affords the ability to form an olfactory image of an object and also the ability to attend to odors. However, the neuronal circuit mechanisms underlying the attentional function in human olfaction were not yet revealed. Caretta and Mucignat-Caretta, the authors discuss that chemosensory dysfunction has been observed in various diseases such as neurodegenerative diseases, neuropsychiatric diseases, dysmetabolic diseases, cancer, autoimmune disorders, cardiovascular diseases, kidney, liver, and lung diseases, and poisoning, other than infectious diseases such as COVID-19. In the case of infectious diseases, viruses other than SARS-CoV-2, bacteria, fungi, and protozoa can cause chemosensory dysfunction, and it is not unique to COVID-19. In the pre-COVID-19 era, these symptoms tended to be ignored or under-appreciated because they were considered not life-threatening. The authors discuss that “notably, dysfunction of olfaction correlates with increased mortality and with patient frailty in the general population, possibly mediated by inflammation” and suggest that “putting chemosensory dysfunction on the clinical spot may help in understanding the patient's symptoms and the underlying pathophysiology of complex diseases, involving multiple systems' integrated response”. Changes in the under-appreciated sense of olfaction could be a key sign of complex diseases that better receives more clinical attention.COVID-19 has had a significant impact on the chemical senses of many patients. So many COVID-19 patients experienced chemosensory dysfunction that the symptoms of chemosensory dysfunction became very well known to the public compared to the pre-pandemic time, causing an illusion that olfactory dysfunction is typical for COVID-19 but not for other diseases. In the review article by HK, TH, FI, MY, SK, and KK wrote the draft of the editorial. All authors revised the manuscript and approved the final version of it.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.


Atherosclerosis (AS) features include progressive hardening and reduced elasticity of arteries. AS is the leading cause of morbidity and mortality. An increasing amount of evidence showed that epigenetic modifications on genes serve are a main cause of several diseases, including AS. Histone deacetylases (HDACs) promote the deacetylation at lysine residues, thereby condensing the chromatin structures and further inhibiting the transcription of downstream genes. HDACs widely affect various physiological and pathological processes through transcriptional regulation or deacetylation of other non-histone proteins. In recent years, the role of HDACs in vascular systems has been revealed, and their effects on atherosclerosis have been widely reported. In this review, we discuss the members of HDACs in vascular systems, determine the diverse roles of HDACs in AS, and reveal the effects of HDAC inhibitors on AS progression. We provide new insights into the potential of HDAC inhibitors as drugs for AS treatment. As a critical potential pathology of cardiovascular disease (CVD), atherosclerosis (AS) is characterized by the progressive hardening and reduced elasticity of arteries; AS is a leading cause of morbidity and mortality . Its proAn increasing amount of evidence indicated that epigenetic modifications on genes are the main cause of many diseases, such as, cancer, and CVDs . Epigene+ to catalyze the deacetylation reaction due to their conserved catalytic domain, whereas other HDACs rely on the binding of zinc molecule as an activator  are a main type of cells in blood vessels that modulate vascular tone, blood coagulation, and mediate inflammatory reaction . HDACs aClass IIa HDACs are involved in vascular homeostasis response to signals in the modulation of gene expression . For insFoxo transcription factors repressed its transcription and restrained EC proliferation, migration, and neovessel formation  is necessary in the formation of neointima and arteriosclerosis . FollowiIn addition, VSMC migration is tightly related to vascular remodeling, which is likely to trigger AS progression . MechaniAlso, the formation and the accumulation of lipid-loaded foam cells is the critical step in the pathophysiology of AS in the vascular wall . The uptThe inversion of macrophage to foam cells plays a pro-atherosclerotic role in the AS process . The macMonocytes and macrophages are critical driving factors in the inflammatory disease process . They plTranslocation of circulating monocytes to the artery wall is one of the prominent phenotypes in AS in endothelial dysfunction and lipoprotein retention . Upon diHistone acetylation also plays an important role in the cholesterol metabolism of macrophages . AlteratLDLR−/− mice, as a general AS mice model, were fed with atherogenic diet and exhibited elevated HDAC3 and HDAC9 expressions during monocyte differentiation to macrophages . Although the inhibition of HDACs in macrophage brought about beneficial effects to AS, the broad usage of these inhibitors is limited by the observation that TSA unexpectedly promoted the progression of plaque expansion in an AS mouse model . This rese model . Also, tTreatment with TMP195, a selective inhibitor of Class IIa HDAC, suppressed critical inflammatory pathways and mitigated atherogenesis in advanced stage AS, thereby offering a novel therapeutic strategy for reducing the consequence of vascular inflammation . AnotherAS is a common pathological basis of cardiovascular and cerebrovascular diseases and seriously endangers human health. With the further understanding of the pathogenesis of AS, an increasing amount of evidence suggested the important role of HDACs in AS. The effects of HDACs on atherosclerosis are complex and multifaceted. In ECs, SMCs, and even macrophages, HDACs play different roles in regulating cell proliferation, migration, apoptosis, differentiation, inflammation, and oxidative stress . It is dIt is well known that the majority of existing or clinically available HDAC inhibitors are generic . The dev


Neurotrophic factors, including neurotrophins and neuropeptides, are secreted proteins that regulate the survival, development, and physiological functions of neurons in both the central and peripheral nervous systems. These factors are not only essential for normal neuronal activity but may also play a role in neurodegeneration following trauma, ischemia, and neuroinflammatory reactions. A deficiency of neurotrophic factors or the deregulation of their cognate receptors is causally associated with the onset and progression of neurodegenerative diseases, i.e., Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). In addition to neurodegenerative diseases, neurotrophic factors are also involved in the modulation of cellular processes in the peripheral nervous system and participate in disorders in various tissues, such as muscle, and the cardiovascular system.Cells summarizes the current knowledge regarding the roles of different neurotrophic factors in health and various diseases, focusing on the complex cell biology and pharmacology of these factors on the cellular, molecular, and clinical levels.This Special Issue of The work of Sebastiano Cavallaro  and his Interestingly, the genes in the apoptosis/survival core set are significantly correlated with neurological, psychiatric, and oncological diseases and encode therapeutic targets whose modulation may exert anti-apoptotic or pro-survival effects.Among the neurotrophic factors, nerve growth factor (NGF), which regulates neuron survival and differentiation, has been extensively studied for its neuroprotective effects, especially in AD, in which NGF plays a central role .In our studies , we inveIn the brain, NGF regulates not only neuron survival and differentiation but also glial and microglial functions and neuroinflammation. Antonino Cattaneo and his group  found thOn the peripheral level, NGF exerts pleiotropic effects on various cell types and tissues, including skeletal muscle. Marco Segatto and coworkers  examinedAnother member of the neurotrophin family, brain-derived neurotrophic factor (BDNF), has been shown to be involved in numerous neurodegenerative and neuropsychiatric disorders by regulating axonal guidance, promoting synaptic plasticity and neurite growth, and facilitating long-term potentiation .In the review conducted by Carmel Matrone et al. , the funThe paper of Patrizia Campolongo and her group , which eIn addition, BDNF is involved in the homeostasis of the cardiovascular system. The role played by BDNF Val66Met polymorphism in myocardial infarction was investigated by Stella Barbieri and coworkers . Using mAnother neurotrophic factor studied in this Special Issue is epidermal growth factor (EGF) and its related tyrosine kinase receptor (EGFR). Cecilia Bucci and collaborators  investigLast but not least, the involvement of vascular endothelial growth factor (VEGF) in depression was investigated by Daniela Pollak and coworkers using a model of maternal immune activation in rats (MIA). The offspring developed depression-like behavior associated with the decreased expression of VEGF receptor 2 (VEGFR2) in the hippocampus . In adulOverall, the papers published in this Special Issue offer new insights into this scientific field and illustrate the key roles that trophic support can play, both from a physiological point of view and in the development of pathologies that are not limited to the central nervous system but also relate to various organs and tissues, stimulating further research.


Due to its undisputed capacity of triggering brain processes with great temporal resolution , direct brain stimulation has developed into a medical and scientific field—the Neuromodulation field—with a vast constellation of efficacious therapeutic techniques and applications. Despite decades-long scientific efforts leading to knowledge advancement, the challenging complexity of the interaction between external stimuli and neurobiology has hindered the full understanding of the mechanisms underlying therapeutic effects. This jeopardizes the choice of stimulation parameters and protocols, impairs a more rational technology design, and thus has an important impact on therapeutic efficacy, efficiency, and safety. Fortunately, unprecedented development of neural interfaces and computational methods for analysis and simulation of neural systems has enabled scientists, technologists, and practitioners to carry out much-refined “precision-neuroengineering” versions of neurostimulation. This Research Topic aims to inform readers on some of the recent contributions that aid to the still ongoing effort of making the transition from historical empiricism toward rational design of techniques and technologies associated with Neuromodulation.in silico and in vivo, with animals and in humans, using stimuli of different physical modalities, including electrical fields, magnetic fields, and ultrasound. They have been applied to different anatomical targets, both within the central and peripheral nervous systems, in invasive, semi-invasive, and non-invasive modalities, in order to assess the effects on neurological disorders, on neural functions, or yet on general properties of neural tissue. This Research Topic includes original research papers, a case report, and a review.The neuromodulation field is very diverse, with distinct methods, targets, applications, and investigative strategies, and the papers selected for this compendium bear testimony to this statement. Experimental studies in this Research Topic were carried out Yuan et al. used hippocampal CA1 of rats in order to investigate in vivo the mechanisms of activity suppression induced by High-Frequency Stimulation (HFS), which is the mainstream protocol adopted in DBS. Using local field potentials and multi-unit neural electrophysiology, the authors report a series of changes in the morphology of population spikes induced by different combinations of antidromic and orthodromic axonal stimuli; which suggests an “antidromic invasion” of propagating action potentials as a possible mechanism for the sustained suppression of activity in the neuronal soma.Electrical stimulation directly applied to the central nervous systems, clinically termed Deep Brain Stimulation (DBS), is certainly the flagship of neuromodulation methods. Although largely studied and employed, full understanding of its therapeutic mechanisms is still lacking. Zhao et al. used a combination of such tES methods, namely Transcranial Direct Current Stimulation (tDCS) and Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), as a means to improve working memory function in humans. The study not only suggests novel venues for pursuing neuromodulation clinical applications by the combination of techniques but also points to a new perspective for the understanding of the therapeutic mechanisms . These thoughts resonate with several other research data suggesting that Large-Scale Integration of neuronal networks may be modulated by using appropriate spatial and temporal patterns of electrical stimulation.A major limitation of DBS is its invasiveness and the risks associated with the surgical implantation of stimulation electrodes. Collectively called Transcranial Electrical Stimulation (tES), a series of non-invasive neuromodulation techniques employ scalp electrodes for induction of electrical currents in cortical regions with distinct applications, ranging from treatment of psychiatric disorders to cognitive enhancement. Khatoun et al. describe in silico evidence for a semi-invasive alternative in which a penetration effect is achieved by interferential stimulation, i.e., by simultaneously delivering electrical waveforms of slightly different frequencies and phases generated by pairs of electrodes positioned on the surface of the skull. This disruptive novel method is termed interferential epicranial electrical stimulation (IF-ECS). Using a realistic computational model of the human head, the authors carried out a finite-element computation to resolve electrical fields and investigate the focality of IF-ECS compared to conventional tES.Conversely, tES is criticized for its limited focality and inability to affect deeper areas of the brain. In their work, Starnes et al. report a case of a 48-years old patient with refractory epilepsy treated acutely and in follow-ups with repetitive TMS (rTMS) together with the investigation of sleep electroencephalography (EEG) biomarkers. Robust seizure control was reportedly attained during treatment and in the ensuing months. Moreover, changes in EEG biomarkers provided evidence of rTMS effects on cortical excitability while bringing about novel insights into its mechanisms of action, including those related to brain connectivity and neural plasticity. As an aftermath, the use of TMS may also be explored as a probing stimulus for detecting abnormal responses, thus working itself as a biomarker for diagnosis and predicting neuronal instability.Other approaches in neuromodulation are carried out using non-electric physical effects as a means to deliver stimulation without any kind of contact with human tissue. This is the case of Transcranial Magnetic Stimulation (TMS) capable of generating electrical currents in the brain after electromagnetic induction imposed by external electromagnetic coils. TMS is under extensive investigation and also severe peer scrutiny. To provide evidence of therapeutic efficacy, Dell'Italia et al. contributed a comprehensive review on Low Intensity Focused Ultrasound (LIFU), a novel neuromodulation technique that has attracted a lot of attention recently. Of great importance, authors dedicate great effort in order to unraveling the underpinnings of its therapeutic effect by reconciling the empirical evidence with the mechanistic investigation. They review the neurophysics  and also the electrophysiology of LIFU to put forward the idea that neuronal intramembrane cavitation excitation (NICE) is possibly a major driving force underlying the effects of LIFU, even if throughout literature there are results that contest such findings.Finally, in silico studies , the importance of investigating mechanisms of action in different levels of brain organization , including neural plasticity-related mechanisms , and the validity of thinking outside the box in the search of novel forms of modulating the brain activity .Overall, the papers included in this Research Topic represent a concise but very interesting sample of the vibrant field of neuromodulation literature reporting efforts toward the development of more rational precision-tuned designs of technologies and methods. In fact, this collection brings up key messages to the field, including the undisputed value of detailed theoretical All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.VC was supported by the Marie Skłodowska-Curie Individual Fellowship MoRPHEUS, Grant Agreement no. 101032054, funded by the European Union under the framework programme H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions. MM is a recipient of CNPq  research fellowship.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.


The decline in cardiac contractility due to damage or loss of cardiomyocytes is intensified by changes in the extracellular matrix leading to heart remodeling. An excessive matrix response in the ischemic cardiomyopathy may contribute to the elevated fibrotic compartment and diastolic dysfunction. Fibroproliferation is a defense response aimed at quickly closing the damaged area and maintaining tissue integrity. Balance in this process is of paramount importance, as the reduced post-infarction response causes scar thinning and more pronounced left ventricular remodeling, while excessive fibrosis leads to impairment of heart function. Under normal conditions, migration of progenitor cells to the lesion site occurs. These cells have the potential to differentiate into myocytes in vitro, but the changed micro-environment in the heart after infarction does not allow such differentiation. Stem cell transplantation affects the extracellular matrix remodeling and thus may facilitate the improvement of left ventricular function. Studies show that mesenchymal stem cell therapy after infarct reduces fibrosis. However, the authors did not specify whether they meant the reduction of scarring as a result of regeneration or changes in the matrix. Research is also necessary to rule out long-term negative effects of post-acute infarct stem cell therapy. Ischemic heart disease is one of the most common causes of death worldwide . Its mosThe objective of the literature review was to determine whether treatment with mesenchymal stem cells after myocardial infarction has a negative, neutral or beneficial effect on diastolic function and regulation of the extracellular matrix.Increased fibrosis was observed in both the infarct zone (IZ) and the non-infarct zone (NIZ). In the infarct zone, successive reparative fibrosis  was observed ,7. In thFibroproliferation is a tissue defense aimed at quickly closing the damaged area and maintaining the integrity of the heart. Balance in this process is of paramount importance. The reduced post-infarction response causes scar thinning and more pronounced left ventricular remodeling, while excessive fibrosis (as mentioned above) leads to impairment of heart function. The process of excessive fibrosis results from increased collagen synthesis, which outweighs unchanged or reduced degradation ,10,11. FCardiac insult rapidly activates the matrix metalloproteinases (MMPs), leading to ECM fragmentation. These fragments act as bioactive pro-inflammatory matrikines . In the Fibroproliferation in the infarct zone ispresented in In the last stage, 1.5 months and later, fibrosis also develops in the NIZ zone . In the Ultrasonography is a very helpful diagnostic tool. It enables the monitoring of morphological and functional changes of the heart muscle, along with the assessment of the regional systolic and diastolic functions of the left ventricle. Assessment of left ventricular diastolic dysfunction (LVDD), according to the guidelines of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI), is mainly based on six indicators: E-wave, E/A ratio, septal or lateral e′, mean E/e′, left atrial index volume (LAVI) and peak tricuspid velocity (TRpV) ,37. ThesHowever, other means, such as cardiac MRI and cardiac catheterization, can be more accurate in terms of quantitative assessment and accurate diagnosis of diastolic dysfunction and assessment of cardiac fibrosis. The diastolic function is closely related to the heart rate and rhythm, atrial function (mainly systolic), ventricular compliance, preload and atrioventricular valve function. Diastolic dysfunction is therefore a reflection of impaired left ventricular relaxation, resulting from its increased stiffness (advanced stages) and increased filling pressure (even more advanced stages) ,38.The development of regenerative medicine and stem cell treatment of coronary heart disease has become a matter of interest for many scientists. It has been observed that, after myocardial infarction, the number of circulating endothelial progenitors CD34+ and CD133+ KDR and mesenchymal cells increases . It has The key factor affecting the diastolic dysfunction of the myocardium as a result of myocardial infarction and dysregulation of the ECM in the context of MSC therapy is the type of stem cells supplied. Some stem cells seem to have greater differentiation capacity, while other may have greater paracrine activity or greater potential to stimulate neovascularization. It was reported that MSCs obtained from the subcutaneous white fat tissue of the abdomen of a pig , injected into a pre-planned area, improved left ventricular systolic function and reduced the scope of the infarction . It alsoMany studies indicate a low immunogenicity of MSCs, thanks to which a single transplant is well tolerated by the recipient organism. However, repeated administration of MSCs may result in the production of all antibodies. Von Bonin et al., reported that the transplant of MSCs, which had contact with fetal bovine serum (FBS), induced the production of antibodies against FBS in the blood of the recipient. It is worth emphasizing that FBS is often used in the MSC culture medium. Thus, MSCs are dualistic in nature.Research shows that, thanks to the use of the latest pharmacological treatment methods on people with MI, we are able to eliminate clinical symptoms, but we are not able to eliminate fibrosis ,47. The Despite significant progress in this method of treatment, cell transplants still have an insufficient degree of implantation in the damaged heart and insufficient survival in the area of damage. In the years 2010–2020 several randomized and multicenter studies of the treatment of ischemic heart disease were carried out, using mainly autologous bone marrow-derived mononuclear cells, but also selected bone marrow cells. All these studies showed no additional benefit over standard therapy ,63,64,65An adult heart muscle has more fibroblasts compared to resident heart progenitor cells . Therefore, the concept was developed to increase the endogenous regenerative potential of an adult heart, performed by reprogramming fibroblasts with the use of retroviruses into ESC-like cells  and then into new cardiomyocytes . Using gExcessive cardiac fibrosis, associated with diastolic dysfunction, is still a clinical problem. There has been no uniform approach to remodeling therapy for several decades. Preventing post-infarction ECM remodeling seems to be very important, because it prevents such dangerous consequences as left ventricular dilatation and rupture ,6,15,73.In conclusion, cellular therapy for heart regeneration has much room for improvement before being considered an affordable, widely available, safe and effective clinical approach. It seems that studies should be carried out at this stage on animal models, as the effects of both non-hematopoietic and hematopoietic stem cells may differ in vitro and in vivo. Long-term research performed to rule out long-term negative effects of post-acute MI stem cell therapy, including diastolic failure, will also be necessary.