COVID-19 is a highly contagious and highly pathogenic disease caused by a novel coronavirus, SARS-CoV-2, and it has become a pandemic. As a vulnerable population, university students are at high risk during the epidemic, as they have high mobility and often overlook the severity of the disease because they receive incomplete information about the epidemic. In addition to the risk of death from infection, the epidemic has placed substantial psychological pressure on the public. In this respect, university students are more prone to psychological problems induced by the epidemic compared to the general population because for most students, university life is their first time outside the structure of the family, and their mental development is still immature. Internal and external expectations and academic stress lead to excessive pressure on students, and unhealthy lifestyles also deteriorate their mental health. The outbreak of COVID-19 was a significant social event, and it could potentially have a great impact on the life and the mental health of university students. Therefore, it is of importance to investigate university students’ mental health status during the outbreak of COVID-19.The principal objective of this study was to investigate the influencing factors of the psychological responses of Chinese university students during the COVID-19 outbreak.U test for two independent samples and binary logistic regression models were used for statistical analysis.This study used data from a survey conducted in China between February 21 and 24, 2020, and the data set contains demographic information and psychological measures including the Self-Rating Anxiety Scale, the Self-Rating Depression Scale, and the compulsive behaviors portion of the Yale-Brown Obsessive-Compulsive Scale. A total of 2284 questionnaires were returned, and 2270 of them were valid and were used for analysis. The Mann-Whitney P=.02), past medical history , and compulsive behaviors  contributed to the risk of mental health issues. Older students , regular daily life during the epidemic outbreak , exercise during the epidemic outbreak , and concern related to COVID-19  were protective factors for mental health issues.Our study surveyed 563 medical students and 1707 nonmedical students. Among them, 251/2270 students (11.06%) had mental health issues. The results showed that contact history of similar infectious disease (odds ratio [OR] 3.363, According to the study results, mental health issues have seriously affected university students, and our results are beneficial for identifying groups of university students who are at risk for possible mental health issues so that universities and families can prevent or intervene in the development of potential mental health issues at the early stage of their development. A novel coronavirus pneumonia disease, COVID-19, spread very quickly across China in early 2020 . The WorCOVID-19 has brought the risk of death from infection and unbearable psychological pressure to people worldwide . PreviouAn essential part of the population is university students, who are under heavy study pressure and have unhealthy lifestyles; more importantly, the university stage is a stage of transition to maturity in life development. During university studies, the social knowledge that students have acquired may be insufficient to understand the pandemic due to the limited social activities of students compared with that of working adults . TherefoTherefore, the aim of our study is to investigate the mental health of university students and its influencing factors during the COVID-19 pandemic on groups of both medical and nonmedical students. In this study, we conducted a survey of the targeted sample with the aims to explore risk factors that contributed to mental disease during the pandemic and to provide evidence for psychological intervention programs for university students. This research is essential for students’ healthy growth and is an effective response to future work and mental health interventions for students.The targeted population included medical students from 57 universities in China. In this study, a cross-sectional survey was developed, and anonymous web-based questionnaires were used to investigate students’ mental health status during the COVID-19 epidemic. A snowball sampling strategy was used; the web-based survey was first distributed to medical students, and they were encouraged to pass it on to others. A total of 2284 questionnaires were returned, and 14 of them were excluded because the respondents did not fill in the answers completely or did not meet the criteria of the survey; for example, some respondents were teachers and not students. A total of 2270 valid questionnaires were finalized in the study, including surveys from 563 medical students and 1707 nonmedical students.The questionnaire contained the demographic information and psychological measures, which include the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), and the compulsive behaviors part of the Yale-Brown Obsessive-Compulsive Scale (YBOCS).The questions on demographic information in this study were related to gender, age, whether the respondent is an only child, ethnicity, place of residence, region of residence, whether the respondent has participated in volunteer work, contact history of similar infectious disease, past medical history, regularity of daily life and exercise during the epidemic, and concern about COVID-19. The geographical distribution map of the participants was depicted by ArcGIS software (Esri), and the cutoff points for classification were based on the Jenks classification technique as employed in ArcGIS, version 10.5.The SAS and SDS ,28 were The YBOCS was developed to remedy problems with existing rating scales by providing a specific measure of the severity of symptoms of obsessive-compulsive disorder (OCD) . This meU test, a type of nonparametric test, was used to explore the significant associations between sample characteristics and mental health issues during the COVID-19 epidemic. Binary logistic regression analysis was conducted for dependent variables  and independent variables , and we set the level of statistical significance as P<.05.Data were analyzed using SPSS, version 26.0 (IBM Corporation). According to the data type, the Mann-Whitney This study was conducted in compliance with the Declaration of Helsinki’s ethical principles and its later amendments, and the study was reviewed and approved by the Ethics Committee on Human Experimentation of China Medical University (EC-2020-KS-025). The study procedures followed ethical standards. The participants were informed of the study protocol, and consent was received from all the participants. All participation was voluntary and anonymous. Confidentiality was ensured in processing personal data and maintaining individual records.The characteristics and other demographic information in the valid sample of 2270 respondents are summarized in U test shows that age, contact history of similar infectious disease, past medical history, compulsive behaviors, the regularity of daily life during the epidemic outbreak, exercise during the epidemic outbreak, and concern about COVID-19 were correlated with mental health issues , as shown in P>.05).The Mann-Whitney P<.05) in the Mann-Whitney U test were entered into binary logistic regression model 1 as independent variables for mental health issues. Likewise, all the other above factors were entered into the binary logistic regression model in order of P value from small to large  goodness-of-fit statistic for comparing models, model 1 (AIC=1397.629), with the lowest AIC statistic, is the model with the best fit.The above 7 factors  that had a significant association . The analysis indicates that age , regular daily life during the epidemic outbreak , exercise during the epidemic outbreak , and concern about COVID-19  were protective factors for mental health issues, as shown in P=.02), past medical history , and compulsive behaviors  were risk factors for mental health issues; this finding showed that students with these three conditions were more likely to have mental health issues.As shown in In our study, we analyzed the psychological responses and associated factors, including risk factors and protective factors, of both medical and nonmedical students after the outbreak of COVID-19. We found that past medical history, contact history of similar infectious diseases, and compulsive behaviors contributed to the risk of mental health issues. Maintenance of regular daily life and exercise during the epidemic outbreak, older age, and high levels of concern (>1 hour per day) about COVID-19 were protective factors for mental health issues.The COVID-19 outbreak is the largest outbreak of atypical pneumonia since SARS in 2003 in terms of the number of infection cases and time of spread . COVID-1A few studies reporting the psychological conditions of college students or medical students during the COVID-19 outbreak emerged during the preparation of our manuscript. Copeland et al  investigOur study focused on the psychological status of university students and concluded that university students with compulsive behaviors are more likely to have mental health issues, which confirmed the conclusions of previous research. The research has suggested that youth with OCD are at risk of experiencing comorbid psychiatric conditions, such as depression and anxiety . StudentUniversity students with irregular daily life during the epidemic outbreak were more likely to have mental health issues, which is similar to previous research results. Previous studies have suggested that with the increasing pressure of modern life and irregular lifestyles, depression has become an increasing threat to human health. Studies have also suggested that better mental health at baseline was predicted by a lower body mass index, a higher frequency of physical and mental activities, nonsmoking, a nonvegetarian diet, and a more regular social rhythm . StudentOur study also indicates that students with a contact history of similar infectious diseases are more likely to have mental health issues because this experience may cause students to worry about whether they have been infected, and medical students are more likely to be exposed to similar diseases in clinical work. Previous studies also suggested a significant association with anxiety for people whose contact histories included contact with an individual with suspected COVID-19 or with infected materials .This study indicates that students who exercised during the epidemic outbreak were less likely to have mental health issues. Studies have suggested that physical exercise is associated with greater cardiovascular fitness, improved muscle strength and endurance, and reduction of depression and anxiety . StudentPrevious studies have suggested that female and older students are more likely to have mental health symptoms ,12; womeFor family and society, these risk variables that cause mental health issues are key factors for early judgment of university students’ psychological problems, and the results also provide the theoretical basis for formulating intervention measures. Schools, families, and the government should provide more care and support to university students during the epidemic.Given the limited available resources and the time of the COVID-19 outbreak, the study adopted the snowball sampling strategy, which is not based on randomly selected samples. Additionally, the researchers did not conduct a prospective study that would provide a specific measure to support the needs of targeted public health initiatives.During the outbreak of COVID-19, some university students experienced mental symptoms. Past medical history, contact history of similar infectious disease, and compulsive behaviors were risk factors for mental health issues. Older age of the students, regular daily life, and exercise during the epidemic outbreak were protective factors against mental health issues. A high level of concern (>1 hour per day) about COVID-19 was also a protective factor.These findings are beneficial for identifying the groups of university students at risk for possible mental health issues, and they provide a theoretical foundation for the formulation of relevant interventions so that universities and families can prevent or intervene in the development of mental health issues among students at the early stage of the disease. Likewise, the findings are essential for education and public health epidemic prevention. In short, students require more attention, help, and support from society, families, and universities during the COVID-19 pandemic.The data and materials used in this study are available upon request from the author.


Governed through the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) since 1995, the current medical R&D system requires significant trade-offs between innovation and high monopoly prices for patented drugs that restrict patient access to medicines. Since its implementation, few amendments have been made to the original TRIPS agreement to allow low- and middle-income countries (LMICs) to facilitate access by generic manufacturers through flexible provisions, such as compulsory licensing and parallel import. Although a useful policy tool in theory, the routine use of TRIPS flexibilities in LMICs in the procurement of new essential medicines (EMs) is regarded as a ‘last resort’ due to strong political response in high-income countries (HICs) and new trade agreements’ restrictions. In this context, access-oriented biomedical Public-Private Partnerships (PPPs) have emerged. More recently, leading multilateral health organizations have recommended different types of intellectual property (IP) interventions, voluntary biomedical patent pools, as strategies to reduce prices and increase the diffusion of novel EMs in LMICs. Nevertheless, the recent Ebola and COVID-19 outbreaks highlight growing concerns regarding the use of TRIPS flexibilities and the limited success of voluntary mechanisms in promoting access to medicines in the Global South amidst health crises. This review aims at describing the state-of-the-art empirical research on IP-related options and voluntary mechanisms applied by emerging PPPs to guarantee timely and affordable access to EM in LMICs and reflect on both models as access paradigms. Some suggestions are put forward for future research paths on the basis of these analyses and in response to contemporary debates on waiving key IP rights on COVID-19 therapies, diagnostics, and vaccines. It can be granted on any ground, among which public health emergencies, stockouts, unaffordable prices, and patent holder’s refusal to license . Nev. Nev7].  in 2008 . While eislation . Of note, patents are only one aspect of IP in the global biomedical R&D. During the 1990s, access-to-medicines advocates often considered patents as the main problem to solve, whereas the “know-how” and trade secrets are often the main barriers to be considered today, as they may further delay generics’ entry to the market . These iThis brings us to the core problem preoccupying governments, health organizations, and companies: as pointed out by numerous prominent authors and health organizations, the current biomedical R&D system as governed through TRIPS requires significant trade-offs between incentives to innovation (IP and market exclusivities) and the high prices that restrict patient access to medicines ,12,13,14Box 1A wide range of studies have looked at the complex impact of implementing TRIPS and newer stringent free trade agreements regimes and the use of TRIPS flexibilities on access to medicines from the perspectives of economics, public health, and law. Key findings from recent studies and three systematic reviews ,18,19 arTrade Treaties and Access to Medicines: Islam and colleagues [lleagues  have reclleagues  found thlleagues .TRIPS Flexibilities as Safeguards to Public Health: The use of CLs has peaked in the years 2004–2008, in conjunction with the Doha declaration and increasing public moral outrage over the death toll of HIV/AIDS [HIV/AIDS . In totaHIV/AIDS . Most ofHIV/AIDS . AnotherHIV/AIDS , includeHIV/AIDS . HoweverHIV/AIDS .In the current system, to return their investment in development, companies charge a monopoly price for new patented medicines, which is often much higher than the cost of production ,24,25,26TRIPS created an incentive system that does not meet the need for investments in new health technologies that are marginally profitable such as therapies for diseases common among the poor and rare diseases, nor does it meet the challenges of accessing treatments for people and populations with limited purchasing power . In the With an out-of-balance medical IP system and the use of TRIPS flexibilities being restricted, access to EMs in LMICs is increasingly relying on donation-based biomedical Private-Public Partnerships (PPPs) between two or more multi-sectoral bodies focusing on the pooled procurement and delivery of medicines ,30. SimiMedsPal). Both databases are a precedent of transparency in the pharmaceutical field and potentially contribute to more informed decisions by governments and international donors regarding the procurement of legally produced generics at lower costs [In this context, leading bodies such as the World Health Organization (WHO) and the Lancet Commission on Essential Medicines Policies have recently recommended on biomedical patent pools as a different type of voluntary practice to promote early generic entry and overcome IP barriers to health . In 2010er costs ,34.The MPP initially focused on patents related to HIV and expanded its model to license products related to HCV, tuberculosis (TB) medicines in recent years. Between 2010 and 2021, the MPP has signed agreements with ten patent-holders and more than 25 generic manufacturers for 13 priority HIV antiretrovirals (ARVs), one HIV technology platform, three HCV direct-acting antivirals (DAAs), and one TB treatment. Over the next five years, the MPP strategic plan is to become a general patent pool for patented small molecules on the WHO Model List of EMs . In addiCurrently, the MPP licenses with branded firms usually cover about 90–100 countries, including all sub-Saharan African countries and Djibouti . InclusiFrom an economic perspective, few authors noted that the MPP is substantially different from patent pools in other fields, such as software and electronics . In thesDuring the discussions on the COVID-19 vaccine patent waiver proposal put forward by India and South Africa, the persistent debate about the current design of the global medical R&D system and its adverse consequences on public health and economic inequalities has peaked . As of DWhile there is a large body of evaluative literature on the effects of the use of TRIPS flexibilities on the diffusion of new drugs in LMICs, the theoretical and empirical literature on biomedical patent pools and additional voluntary IP mechanisms is new and limited in scope. The broad aim of this review is to explore the state-of-the-art of the empirical support for the use of medicines patent pools and bilateral voluntary IP agreements to promote timely and affordable access to EMs in LMICs. Subsequently, we attempt to identify remaining gaps and make some suggestions regarding future research.We conducted a non-structured narrative review of the empirical evidence addressing voluntary IP licensing models to increase affordability and availability of new and existing EMs. Although systematic reviews are placed higher on the hierarchy of evidence-based public health in answering specific research questions, non-systematic reviews play an important role in addressing a topic in wider ways ,51. The The literature databases PubMed (MEDLINE), Scopus, and EconLit were searched in October and December 2021 to identify relevant publications in English, without limits of date of publication or geographical settings. Additional gray literature and scholarly materials, including working papers, dissertations, and book sections, were manually searched using institutional websites, Google Scholar, and snowballing through review of references in the identified publications. Full information on MeSH terms, keywords, and Boolean operators used and search strategy developed for each database is provided in the After removing duplicates using Covidence and Mendeley online platforms, SM conducted title and abstract screening. In the next stage, both authors independently participated in full-text review and selection and reached a consensus on the studies to be included.Data on research objectives, methodology used, data sources and type (proprietary or publicly available data), population, period and medicines covered, outcomes of interest, controls, main findings, and key limitations were extracted from selected references using an Excel form. Findings from the included studies were synthesized using tables and a narrative summary.The reviewed literature is situated at the intersection of several broader strands of the literature in economics of innovation, patent pools, and healthcare economics, namely healthcare affordability. A PRISMA flow-diagram  reports We identified eight papers for review; all were published between 2017 and 2021 and used data ranging from 2004 to 2020 (six years prior to the establishment of the MPP in 2010 and a decade after). All studies performed quantitative analysis, including four studies that applied a quasi-experimental approach using difference-in-difference ,36,54,55In the following section, we describe key findings, organized according to the following themes: (1) generic drug diffusion, including the share of generics and total quantity of drugs purchased; (2) actual and projected cost savings; (3) public health impact; and (4) follow-on innovation.In a recent National Bureau of Economic Research (NBER) working paper, Galasso and Schankerman  asked whInterestingly, a cross-sectional study by Beall and Attaran  that linResults of three quasi-experimental studies indicate that after inclusion in the pool, the total quantity of EMs purchased by procurement agencies  in MPP territories is likely to increase a few years after its inclusion compared with LMICs that were not included in the agreement ,36,54. IWang  retrospeA different method to understand the effect of voluntary participation of pharmaceutical firms in licensing agreements is provided in Assefa and colleagues’  capacityOnly one ex-post study we are aware of by Simmons and colleagues  estimateFollowing past literature on the relationship between IP policies and cumulative innovation , Wang  also demThe present review highlights that there has been a notable increase in the number of studies that have explored the multifaceted effects of collaborative IP models, particularly through the MPP, on health and economic outcomes in LMICs. This research attention might reflect how IP and high prices of medicines increasingly affect individuals and societies. A decade after the establishment of the MPP, new findings, mostly tested by using quasi-experimental economic models and health impact assessment simulations using the MPP publicly available data, suggest that patent pooling fostered generic manufacturing, leading to increased generic market shares, total quantity of essential HIV and HCV medicines purchased in countries included in the agreements and improved treatment uptake volumes. The strength of these associations, however, is mostly determined by country characteristics, drug type, time intervals, and health and market outcomes considered. As discussed above, the effects of VLs on actual prices and treatment uptake across countries are challenging to capture. Yet taken together, there is considerable evidence that VLs, namely through the MPP, lower prices through generic competition and improve uptake of EMs. These findings were overall consistent with the broad literature on the role of generics in improving access to medicines ,19,20.Moving one step forward, Wang  suggesteReviewed studies repeatedly reported certain methodological challenges. First, data offer only a few years of observations since most VLs have only been agreed upon during the past decade, and they are mainly addressing medicines for HIV/AIDS and only very few other diseases. A more general problem in the field is the scarcity of transparent data on prices and volumes of generic or branded medicines procured, as well as epidemiological data in some LMICs. Some authors conducted field work to collect price data from multiple public authorities ,57, whilConversely, the evaluations of VL rely on several assumptions while some important contextual factors may have similar effects on drug diffusion, price, and uptake, and therefore might overestimate the effects of VL on access to innovation. Some hard-to-model factors, such as comprehensive transmission dynamics and context of VL negotiations, may have affected quantity purchased, treatment uptake, and price regardless of the VL agreement . FactorsIn the following, we outline several open questions that need to be addressed in future studies to create a more complete picture of the role of voluntary IP models in improving EM accessibility. In particular, as briefly mentioned above, access-oriented biomedical patent pools differ in many ways from patent pools in other technological fields, and more empirical and theoretical research is required to generate a systematic evidence base for the concept from the perspective of public health, global health governance, and economics of innovation.To gain a deeper understanding of the conditions under which such licensing might be most beneficial, future studies need to examine different VL models in varied geographical settings and explicitly test potential adverse effects of VL. First, given the distinct characteristics of voluntary agreements negotiated through the MPP and those granted through bilateral agreements outside the pool between two for-profit companies, and the variation in licensing practices (non-exclusive versus exclusive), duration and geographical scope, it is necessary to compare and separately assess the effects of these practices on access-related outcomes.Secondly, more studies in specific regions and domains of diseases are needed. Although the general potential of the MPP in facilitating generic production and uptake has been documented across a bundle of LICs included in the VL agreements, study designs often mask unique characteristics of countries and regions. One exception is the recent study by Galasso and Schankerman  that invSubsequently, as with any evaluation of any intervention, it is vital to consider and test potential negative results related to each VL approach, alongside all the potential benefits. Several studies reported weak effects of VLs, but more attention is needed to directly test and report potential negative effects. For example, Martinelli and colleagues  describeAnother critical issue requiring future research attention is the lack of qualitative studies evaluating the role of biomedical patent pools and negotiating practices from the perspective of policymakers, health providers, and generic manufacturers in LMICs. Future research is needed to provide insights on how the MPP (and similar initiatives) negotiate specific access-oriented IP clauses and characterize the knowledge transfer models and how these frameworks are applied in practice. Similar studies were previously conducted in the field of early-stage research private-public partnerships ,30,68. DExcept for Assefa and colleagues’  study, sThe introduction of a wide range of innovation policies and the scale of globalized networks of public-private collaborators, supported with unprecedented public funding, contributed to the accelerated development of COVID-19 diagnostics, vaccines and therapies ,71,72. NIn October 2020, India and South Africa, with the support of many developing nations, requested a temporary waiver of key TRIPS provisions for several patented COVID-19 health technologies to ensure rapid generic production and availability in LMICs. Opponents of the waiver, including the EU, UK and Canada, and pharmaceutical industry representatives, argue that such changes to IP regulations would be counterproductive for technology sharing and have a serious chilling effect on inventors . They maAt the outset, we note that to date there have been no CLs or pooled licensing agreements through the MPP for any vaccine . Prompt To increase production and global diffusion of high-quality generic versions of COVID-19 vaccines, a higher level of collaboration and multiple additional non-patent IP and trade secrets need to be addressed through technology transfer, on top of IP licenses . In respLittle empirical evidence has been generated so far on IP flexibilities and population health during the pandemic. More studies are needed to map and better understand the scale of use, effectiveness, and limitations of various collaborative IP models, industry-led responses, and policy tools to overcome market exclusivity barriers to affordable COVID-19 biomedical technologies across LMICs amidst the pandemic.For example, the (relatively) rapid introduction of emergency innovation policies across countries, the expansion of the MPP mandate, and industry-led mechanisms in response to the unmet medical needs across a wide range of countries resulted in countless unplanned natural experiments . Future The topic of IP interventions to increase COVID-19 vaccine diffusion ignites further conceptual and methodological questions for researchers. So far, 22 vaccine developers have directed their efforts into increasing production capacity in their own facilities or through sub-licensing arrangements with at least 130 manufacturers based in 45 countries . Of thesLastly, most COVID-19 health technologies, such as MPP-licensed molnupiravir, were invented in US and UK universities, supported with taxpayer money ,72,83. PThe present review excluded articles written in languages other than English and so important findings and perspectives may have been missed. In addition, the review aimed at presenting a narrative synthesis of recent findings and, importantly, did not attempt at computing effect sizes or include a risk of bias assessment for included papers given the heterogeneity of study designs and objectives. Several other closely related issues could not be addressed in this scope. These include more attention to the complexity of knowledge transfer processes and availability of prequalified manufacturers in LICs, the role of national IP and competition law, and the assessment of other IP-related interventions occurring at pre-approval stages. For instance, non-commercial R&D initiatives with IP commons targeting missing EMs, such as the Global Health Innovative Technology (GHIT) governmental initiative in Japan and product development partnerships such as DNDi, which already developed six new treatments for neglected diseases . These mIn response to the increased interest in interventions to balance IP, our objectives for this paper were two-fold: (i) to review the available evidence for the effectiveness of voluntary licensing practices, mainly through patent pooling, and (ii) to identify knowledge gaps and future research directions.In the current global medical R&D system, governed mainly through the TRIPS agreement, generic drugs often enter the market following the expiration of lengthy patents and market exclusivities. The use of TRIPS flexibilities in LMICs to facilitate affordable and faster access to EMs is increasingly restricted. To compensate for the deficiencies in global policy, non-commercial R&D and pooled IP initiatives have emerged, largely funded by a few high-income countries and the Bill and Melinda Gates Foundation. The present review identified a number of recent studies that tracked access to generic EMs in LMICs before and after the imposition of VLs through the MPP or outside the pool and evaluated these interventions from a public health and economic perspective. Overall, these studies indicate that in 11 years since the first biomedical patent pool establishment, it fostered generic diffusion of several EMs for HIV and, more recently, HCV, benefiting millions of people and achieving impressive financial savings for developing countries and international health organizations. One clear implication is that biomedical patent pools should be encouraged by governments.We highlighted some areas for future exploration to define success formulas and pitfalls of alternative IP models, such as (i) measuring the effects of different VL approaches in different settings, (ii) conducting qualitative interview studies with key stakeholders, (iii) assessing the effects of patent pools on biomedical products affordability at the collective level, (iv) mapping and examining the effectiveness of collaborative IP models and use of TRIPS flexibilities during the COVID-19 pandemic and in relation to global health governance.Lastly, for the avoidance of misinterpretations of findings, we reiterate that while the option of voluntary participation of prominent pharmaceutical in licensing agreements through one operating patent pool is beneficial, it cannot provide a sustainable and comprehensive solution to the underlying fundamental problems and policy failure of a health innovation system relying on market exclusivities. No single IP option can . The MPPThe public debate on the topic of tackling IP barriers to promote health equity is being stifled by the assertion that “there is no alternative” to the current medical R&D system based on market exclusivity—a key cause to problems preoccupying most governments. One main concern is that, in the times before COVID-19, policymakers did not heed the robust empirical findings in the IP-health literature or misinterpreted them. These concerns are crucial to global health today amidst the ongoing pandemic, which has already intensified the existing disparities in living standards and health outcomes in many parts of the world . Echoing


They are part of the tripartite synapse, composed of pre- and postsynaptic neurons and perisynaptic astrocytic processes as a functional unit. There is an increasing evidence that astroglia are involved in the pathophysiology of CNS disorders such as epilepsy, autoimmune CNS diseases or neuropsychiatric disorders, especially with regard to glia-mediated inflammation. In addition to astrocytes, investigations on microglial cells, the main immune cells of the CNS, offer a whole network approach leading to better understanding of non-neuronal cells and their pathological role in CNS diseases and treatment. An in vitro astrocyte-microglia co-culture model of inflammation was developed by in vitro astrocyte-microglia co-culture model of inflammation proved to be suitable as unique in vitro model for pharmacological investigations on astrocytes and microglia with future potential .Astrocytes and microglia are the main cell population besides neurons in the central nervous system (CNS). Astrocytes support the neuronal network  Astrocytes and microglia are the main cell population besides neurons in the central nervous system (CNS). Astrocytes represent the largest glia cell population. They are involved in the formation of the blood–brain barrier, support of the ion, water and neurotransmitter homeostasis as well as regulation of neuronal synaptogenesis . They arMoreover, astrocytes and microglia play an important role in neurological diseases such as multiple sclerosis (MS)  and epilThe involvement of astrocytes and microglia in neuropsychiatric disorders raises the question how these cells besides neurons might be responsive to current pharmacological treatments, especially with link to inflammation. Therefore, this focused mini review will summarize and discuss the major findings of pharmacological investigations in glia culture model of inflammation.via an intermediate form (INT) to the activated form   . The RRTpe, RPT) ; a largepe, RPT) ; the INTpe, RPT) . Under ppe, RPT) . The patpe, RPT) . As a repe, RPT) . Under ipe, RPT) . The effpe, RPT) . The intammation . In the ammation , this frammation  under paammation , more acammation . Moreovenditions . Incubatnditions . In contcultures . Since tch as MS  or Alzhech as MS , this si studied . Besides studied . Of cour studied . Such a  studied .in vitro study focusing on metabolic effects of AEDs showed CBZ-induced stress on primary astrocytes at all concentrations, but low concentrations of GBP did not change the metabolic activities of astrocytes and did not have toxic effects on these cells  expression on inflammatory active astrocyte cultures  is a neuropathological condition caused by acute or chronic liver failure due to hyperammonemia and impaired detoxification of ammonia by the astrocytic glutamine synthetase, resulting in astrocyte swelling . It is kin vitro astrocyte-microglia co-culture model of inflammation developed by in vitro astrocyte-microglia co-culture model of inflammation proved to be suitable as unique in vitro model for pharmacological investigations on astrocytes and microglia with future potential . Even more, astrocytes and microglia as main glia cells are novel therapeutic targets for future treatment perspectives using the glia co-culture model of inflammation.The FSI, FC, and TJF prepared the manuscript. All authors were responsible for concepts and design, contributed intellectually, acquired, analyzed, and interpreted the data, read and approved the submission, and agreed to be accountable for the content of the work.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.


This study evaluated the stress distribution in five different class II cavities of premolar models restored with conventional or bulk-fill flowable composite by means of finite element analysis (FEA) under shrinkage and occlusal loading. An upper validated premolar model was imported in the software, and five class II cavities with different occlusal extensions and dimensions were prepared: horizontal cavity on the mesial surface , mesio-occlusal cavity, mesial cavity , tunnel type cavity and direct access cavity. The models were restored with conventional or bulk-fill flowable resin composite. The tested materials were considered as homogeneous, linear, and isotropic. The Maximum Principal Stress criteria was chosen to evaluate the tensile stress results. The lowest shrinkage stress value was observed in the direct access cavity restored with bulk-fill flowable resin composite (36.12 MPa). The same cavity, restored with conventional composite showed a score of 36.14 MPa. The horizontal slot cavity with bulk-fill flowable showed a score of 46.71 MPa. The mesio-occlusal cavity with bulk-fill flowable had a score of 53.10 MPa, while with conventional composite this was 55.35 MPa. Higher shrinkage stress was found in the vertical slot cavity with conventional resin 56.14 MPa, followed by the same cavity with bulk-fill flowable 56.08 MPa. Results indicated that the use of bulk-fill flowable composite resin more significantly decreased the polymerization shrinkage stress magnitude. The larger the cavity and the volume of material necessary to restore the tooth, the greater the residual stress on enamel and dentin tissue. Caries is a common oral disease caused by initial demineralization of the tooth structure because of bacteria acid production in the presence of fermentable carbohydrates, and following enamel and dentin mechanical resistance loss . The tooCurrently, it is suggested the cavity design should be indicated exclusively by the caries extension, since nowadays the composite resin bond strength with the dental tissues allows a more conservative approach . The priFor these class II cavity models, the use of resin composites as a restorative material is the first option due to its ability to mimic the missing dental tissues, easy handling, proper adhesion, adequate mechanical resistance and mechanical behavior of enamel and dentin . In ordeIn order to study some complex problems, the finite element method can be used for quantitative and qualitative analysis of the mechanical behavior of dental structures ,12. ThusThe null hypothesis was (1): There would be no difference in the proximal cavities’ stress concentration with the application of a bulk or conventional resin composite. (2): The different cavities’ design would not exhibit similar stress magnitudes.A first upper premolar model, previously validated , was impDifferent models of class II cavities with specific extensions, dimensions and final volumes  were preThe CAD models were exported as STEP files to the analysis software . The mesh was created with tetrahedral elements, and the contacts were considered connected . The proPolymerization shrinkage was simulated by thermal analogy . The temFor the models restored with conventional resins, two increments were simulated. For this, the stress was generated in two steps (one for each portion of the resin composite) . A statiThe stress distribution results for all groups are shown as colorimetric graphs in The stress peaks were recorded in two different moments; first, only the polymerization shrinkage stress effect was present as resultant from the resinous material applied to fill the cavity . In the The resultant stress distributions for the models were compared and examined, and the Maximum Principal Stress was designated as analysis criteria. Regardless of the cavity design, the highest stress concentration in the enamel tissue occurred in the cavosurface angle at the restoration margin, except in the vertical slot design. In addition, the residual stress during the resin composite polymerization shrinkage was reflected in models with proportional stress magnitude after the compressive loading application.The most favorable result, with the lowest shrinkage stress, was observed in the direct access cavity before compressive loading (10.09 MPa) and after compressive loading (36.12 MPa) The same cavity, restored with conventional resin, presented a slightly greater (11.13 and 36.14 MPa before and after loading) magnitude of shrinkage stress.Favorable results were also found in the restoration of the horizontal slot cavity, where the bulk-fill flowable was able to reduce the stress in comparisons with the conventional resin composite; however, the stress data were higher than the horizontal slot. Tunnel cavity restorations with bulk-fill showed intermediate results.In comparison with the direct access and horizontal slots, higher stress values were observed in the mesio-occlusal cavity design restoration for the bulk-fill flowable and conventional resin composites.The results most prone to failure were calculated when restoring the vertical slot cavity with conventional resin, followed by restoring the same cavity with bulk-fill flowable. In this case, it was observed that the whole system was compromised, even when the bulk-fill flowable was used.The null hypothesis was that there would be no difference in the proximal cavities restored with the application of a bulk or conventional resin composite. The results showed that different cavity design exhibited different magnitudes, and could affect the dental treatment biomechanics. Thus, both the hypotheses were rejected.The bond strength among restorative materials and dental tissues must be effective at the interface of the restored cavity, mimicking the mechanical properties of lost mineralized tissues and limiting marginal leakage and cusp deflection ,20. MorpThe results of a literature review suggest that composite resin restorations can demonstrate clinically acceptable results in a long-term period of more than 15 years of follow-up . AccordiThe bond strength can decrease at the tooth-restoration interface or at the margins of the restoration, resulting in marginal stains, internal and marginal fissures, micro-cracks, secondary caries and premature restoration loss ,30. RestAccording to the obtained results, cavities adhesively restored with conventional composite resin presented higher residual stress concentrations. Therefore, this result is in agreement with the literature which has reported that high modulus conventional resin composite can promote a significant effect on the marginal microleakage as a shrinkage, debonding or fracturing of the adhesive interface ,34,35.The bulk-fill flowable resin composites showed in this investigation less polymerization shrinkage stress because of the described presence of modulators and polymerization monomers capable to relieve stress ,39,40,41For this study, different types of class II preparations were selected, with the aim of simulating the restorative procedures performed routinely in different patients. Direct access is performed mainly in cases of local carious lesions and with a reduced extension, removing only the necessary tissue with no needs for additional retentive forms. The preparation of the mesial cavity  occurs when there is involvement of the area affected by caries in the proximal region, with access to the rupture of the marginal ridge. In this case, the preparation is self-retaining because the buccal and lingual walls converge towards each other to the occlusal surface. Compared to the vertical slot, the preparation of a horizontal slot is more conservative because it is strictly proximal and can be achieved by buccal or lingual, preserving the occlusal surface and the marginal ridge. The mesio-occlusal cavity, on the other hand, is performed when the carious lesion compromises two sides of the dental structure, with the rupture of the marginal ridge and the occlusal surface. It is a more extensive cavity with a limited c-factor, and in this cavity design, the walls of the proximal box converge towards to the occlusal. In incipient caries located on the proximal surfaces of posterior teeth and with marginal ridges free of lesions, tunnel-type preparations can be performed where the marginal ridge is preserved, and access is granted through the occlusal surface .In a previous study  that aimIn relation to the types of cavities, larger restorations promote a greater increase in stress at the tooth-restoration interface . AccordiThe preparation of a tunnel-type cavity can be considered more difficult compared to the preparation of the other types of class II cavities . It is rAccording to the data obtained in previous reports  and the Some intrinsic limits of the current finite element analysis involve the use of a model with an isotropic resin composite, without defect populations in the material, perfectly bonded in all cavities and with a linear behavior. Despite all the advantages of FEA ,43,44, iThis present study showed that the use of bulk-fill flowable resins could reduce the residual stress of small proximal cavities. In addition, class II preparations of the mesio-occlusal type and vertical slot, due to the size and geometry of the cavity, may present an increase in shrinkage stress and, consequently, greater stress at the tooth-restoration interface.Despite the results reported with the present in silico evaluation, some limitations should be considered when interpreting them. The present analysis did not consider the pH variation simulation, cyclic loading, restoration adhesive failure, biofilm formation, temperature variation or different antagonists. In addition, the simulated materials were not orthotropic or anisotropic materials, and the obtained results were not calculated considering data deviation or systematic error that can be present in biological tissues and complex systems. However, further fatigue lifetime studies should be developed, considering the S–N curve, to provide a more complete in vitro evaluation prior to clinical trials using prospective studies.-Regardless the cavity design, the use of bulk-fill flowable resin composite is a viable option to restore the missing dental tissue.-Smaller class II cavities can be conveniently restored with low shrinkage resin composites to reduce the residual stress and the adhesive failure risk.-Conservative preparations should be performed in order to reduce the volume of resin composite material, and the stress of the direct proximal restorations.Based on this information and despite the limitations of this study, it can be concluded that:


The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated. Excessive weight gain is associated with the presence of cardiovascular risk factors, such as dyslipidemia, impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2D), hypertension, and kidney failure . The incNeural mechanisms have been involved in the pathogenesis of obesity and insulin resistance, particularly sympathovagal imbalance, and the relative prevalence of sympathetic activity has been suggested to play a pivotal role in this complex bi-directional relationship . Among tThe purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system (CNS), providing further insights into the impact of ANS balance on adipose tissue and IR. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.The ANS plays a central role in either the short-term or in the long-term regulation of body weight. Particularly, the short-term regulation of body weight is mainly mediated by the sensation of satiety, through gastric distension, due to the activation of vagal afferent nerves and gut hormones release. However, vagal activity is also involved in this latter pathway, since the activation of vagal afferents has now been recognized, as an early step in the control exerted by gut hormones on nutrient delivery to the intestine, by regulating food intake and gastric emptying  5]. The. The5]. More complex is the bi-directional relationship between obesity and sympathetic activity. In insulin-resistant states, such as in obesity, increased basal sympathetic activity has been reported and correlated with the degree of IR ,8,9, sugThe consequent activation of the sympathetic nervous system (SNS) is associated with important hemodynamic effects on blood vessels, heart and kidney.The stimulatory action of insulin on SNS activity is directly exerted in the brain: in the fasting state, low levels of plasma insulin reduce insulin-mediated glucose metabolism in hypothalamic neurons, resulting in the activation of an inhibitory pathway that suppresses chronically active sympathetic centers in the brain stem. Following carbohydrate intake, the increased insulin concentration stimulates insulin-mediated glucose metabolism in the same neurons, leading to augmented insulin-mediated glucose metabolism, reduction of the inhibitory pathway, and finally stimulation of the sympathetic centers at the brain-stem levels, with a consequent increase in central sympathetic outflow . This meThe direct correlation between muscle basal nerve sympathetic activity and body fat suggests a link between SNS activity and obesity-related IR. Therefore, the prolonged stimulation of the sympathetic system, exerted by hyperinsulinemia in obesity, evokes hemodynamic responses, such as increased heart rate and cardiac output and reduced heart rate variability , which mHowever, a chronic increase in sympathetic outflow has been reported to decrease β-adrenergic responsiveness itself ,18 throuIn conclusion, in the complex regulation of body weight, a pivotal role is played by the ANS, both by the parasympathetic and the sympathetic branch. While the afferent vagal pathways seem to represent the most important link between the gut and the brain, sympathetic activation is involved in lipolysis increase and energy expenditure in white and brown adipose tissue (WAT and BAT), where, however, it results ineffective, in obesity. Sympathetic activation may favor the development of hypertension and organ damage in obesity and lead to overt cardiovascular disease.Leptin is a hormone released by the WAT and has been shown to increase energy expenditure, acting both on the cardiovascular system and BAT thermogenesis via the arcuate nucleus (ARC) of the hypothalamus . The ARCNumerous data support the concept that leptin represents an important regulator of regional sympathetic nerve activity with pathophysiological implications in obesity .Leptin regulates energy balance by decreasing appetite and increasing energy expenditure through sympathetic stimulation . Leptin It has been widely reported that leptin increases the sympathetic outflow to the kidneys, skeletal muscle vasculature and adrenal gland. A study conducted in non-obese rats reported that intravenous or intracerebroventricular (ICV) infusions of leptin increase sympathetic activity in the kidneys and adrenal glands . AccordiObesity is associated with circulating hyperleptinemia as a consequence of leptin resistance, suggesting that obese subjects have resistance to the anorectic and weight-reducing effects of leptin. At the same time, elevated plasma leptin levels may increase blood pressure and contribute to the development of hypertension .Several studies confirmed the link between leptin and hypertension, reporting increased leptin levels in obese hypertensive individuals in comparison to obese normotensive subjects. Moreover, leptin deficiency in humans was associated with obesity and metabolic syndrome, without SNS activation or hypertension. These data confirm a role for leptin-mediated sympathetic activation in the pathogenesis of hypertension in obesity . ConversBased on these findings, Mark et al. suggested a “selective leptin resistance”, in at least some forms of obesity, limited to its metabolic effects (satiety and weight loss), while it retains its sympatho-excitatory effects on the cardiovascular system via the SNS, through actions in the brain region of the DMH . This phMore recently, the evaluation of the differential effects of acute and chronic leptin stimulation on thermogenesis and lipolysis  but alsoThe activation of SNS by leptin occurs after food intake or cold exposure and induces lipolysis in WAT and heat production in BAT. In particular, sympathetic activation results in mobilization from WAT of free fatty acids (FFA), which are then used by BAT to dissipate energy as heat  5]. Stu. Stu5]. Following the above, leptin levels reflect nutritional availability  and it eIndeed, leptin was shown to contribute not only to normal body weight regulation but also to the physiological control of blood glucose levels. It has been recently reported that leptin may improve glucose homeostasis and insulin sensitivity by increasing peripheral tissue glucose uptake and reducing liver glucose production . TherefoThe link between energy balance and fertility has also been investigated. It has been demonstrated that leptin may influence the neural circuits related to reproduction. The study of Hill et al. reported that female mice lacking both leptin and insulin receptors in POMC neurons exhibit lengthened reproductive cycles, follicular arrest, hyperandrogenemia, and are sub-fertile . These dWe may conclude that leptin signalling regulates the plasticity of the sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis. However, the picture of the mechanisms involved in the pathogenesis of obesity is more complex, and within the neural circuity regulating energy balance, the participation of non-neuronal cells, such as glia, has been recently demonstrated . The intThe circadian clock plays a crucial role in many biological processes and is organized in the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and in the peripheral clocks located in peripheral tissues . The light is the main synchronizer for the SCN, which in turn transmits timing signals to the peripheral clocks. In addition, other stimuli such as hormones, nutrients, feeding/fasting state, sleep-wake state, physical activity can affect the circadian rhythm in peripheral tissues .The circadian clock is the main regulator of metabolism and energy homeostasis, and its disruption may lead to metabolic disorders and contribute to overweight and obesity. In animal models, SCN alterations, as well as clock gene mutations, result in dyslipidemia, insulin-resistance and hyperglycemia. In humans, circadian disorders such as deterioration of the sleep–wake cycle due to insufficient sleep, shift work and social jet lag have been shown to be associated with symptoms of the metabolic syndrome, including an impaired glucose tolerance and insulin sensitivity, hypertriglyceridemia and an increase in body mass index (BMI) and mean arterial blood pressure .The presence of circadian clocks in WAT and BAT has been reported, and several pieces of evidence showed that the secretion of leptin is characterized by a circadian rhythm with serum leptin peak levels occurring during the night in mice and humans . It has Interestingly, studies conducted on human adults showed an increase in food intake when sleep is acutely restricted, and food is provided ad libitum . It has Recently, the circadian rhythm of blood pressure has also been investigated in mice and humans . NocturnAs reported in this review, the ANS plays an important role in the regulation of blood pressure but also in the regulation of body weight, satiety and energy homeostasis. In particular, we highlight the pivotal role of leptin in increasing energy expenditure, acting both on the cardiovascular system and BAT thermogenesis through the activation of SNS. In obese subjects, the sympatho-excitatory effects of leptin on the cardiovascular system are maintained while its metabolic effects result ineffective, suggesting that some form of obesity may be characterized by a “selective leptin resistance”. Therefore, in obesity, the failure in leptin action may lead to a reduction of energy expenditure and contributes to weight gain; at the same time, a compensatory hyperleptinemia may favor the development of hypertension and lead to overt cardiovascular disease.Furthermore, the interplay between insulin and leptin plays a relevant role in glucose homeostasis and arterial blood pressure; therefore, a dysfunction of insulin and leptin crosstalk could be related to the alterations of the sympathetic activity and responsible for the subsequent development of hypertension and/or T2D.Moreover, it has been highlighted that disruption of the circadian clock may alter leptin circadian rhythm and synthesis and may induce leptin resistance, causing the impaired regulation of metabolism and energy balance and promoting obesity and metabolic complications. These data place leptin as a major bridge linking circadian control and energy homeostasis.However, the effects of leptin on several neural circuits, including the SNA, require further investigations in order to obtain a more complete picture of the mechanisms involved in the pathogenesis of obesity and its complications.


Depression is a leading cause of disability and affects more than 4% of the population worldwide. Even though its pathophysiology remains elusive, it is now well accepted that peripheral inflammation might increase the risk of depressive episodes in a subgroup of patients. However, there is still insufficient knowledge about the mechanisms by which inflammation induces alterations in brain function. In neurodegenerative and neuroinflammatory diseases, extensive studies have reported that inflammation negatively impacts mitochondrial health, contributing to excitotoxicity, oxidative stress, energy deficits, and eventually neuronal death. In addition, damaged mitochondria can release a wide range of damage-associated molecular patterns that are potent activators of the inflammatory response, creating a feed-forward cycle between oxidative stress, mitochondrial impairment, inflammation, and neuronal dysfunction. Surprisingly, the possible involvement of this vicious cycle in the pathophysiology of inflammation-associated depression remains understudied. In this mini-review we summarize the research supporting the association between neuroinflammation, mitochondrial dysfunction, and bioenergetic failure in inflammation-associated depression to highlight the relevance of further studies addressing this crosstalk. Research on the communication between the brain and the periphery has shed some light on how the peripheral immune system governs our behaviors and emotions. The existence of intricate neuroimmune interactions is now well recognized by researchers and clinicians and has been widely explored in the context of inflammation-induced sickness behavior and inflammation-induced depression . Over thThere have been many studies aiming to test the ability of anti-inflammatory drugs ranging from non-steroidal anti-inflammatory drugs to cytokine antagonists to treat depression as an adjunct to classical antidepressants. However, the results are not always easy to interpret due to insufficient consideration of the efficacy of these drugs on their primary target (inflammation) and the lack of selection of the type of depression to be treated  . In addi2+ homeostasis, generation of free radicals, steroid synthesis, and apoptotic cell death  produced by inflamed microglia or astrocytes inhibits mitochondrial respiration of surrounding neurons by the reversible inhibition of cytochrome  neurons . NO also neurons  and dyna neurons , which p neurons . Particu neurons .N-methyl-D-aspartate receptor (NMDAR) activation  complexes I and II and impairs activity of the mitochondrial ATP synthase . In parttivation . While ltivation . Taken t2+ influx into neurons, which depolarizes the mitochondrial membrane and increases the generation of ROS that can lead to cell death depending on mitochondrial pathways  is susceptible to the effects of ROS generated by the ETC . BecauseIt is important to note that mitochondrial damage can by itself fuel inflammation, with the potential of forming a highly vicious cycle . DamagedTaken together, these observations indicate that inflammation can impair mitochondrial function while dysfunctional mitochondria might drive and/or propagate inflammatory responses, creating a vicious cycle that can compromise neuronal function at the bioenergetic level. Clinical and preclinical studies in biological psychiatry have gathered evidence in favor of mitochondrial dysfunction in major depression, but these results have to be interpreted with caution due to the lack of consideration of the type of depression under study.Multiple lines of evidence indicate that mitochondrial processes are altered in patients with major depression. Depressed patients show mtDNA mutations , higher 2+ handling, and oxidative stress were found to be differentially expressed in the prefrontal cortex of patients with depressive disorders when compared to healthy subjects  reduced sucrose preference and was accompanied by increased mRNA levels of cytochrome oxidase 1 (COX-1) and 3 (COX-3) in the prefrontal cortex . In addiAnother study used an acute model of colitis to induce depression- and anxiogenic-like behaviors in mice . Three dThe symptomatology of patients with inflamed depression is mostly characterized by motivational changes, anergia, and motor slowing , reflectPpargc1a, which encodes for peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), one of the master regulators of mitochondrial numbers and function, counteracted the effects of CNS inflammation.The mechanisms that are responsible for this selective susceptibility are not fully understood but might involve particular features of mitochondria in dopaminergic neurons. First, dopaminergic neurons are under constant oxidative stress due to the auto-oxidation of dopamine (DA) that gives rise to dopamine-quinones and superoxide radicals. Second, borrowing from the research on Parkinson’s disease, the selective loss of dopaminergic neurons from the substantia nigra pars compacta (SNc) can be partially explained by their high basal rate of mitochondrial oxidative phosphorylation and high density of axonal mitochondria, that are accompanied by elevated ROS production . ContrasEven though there is evidence for mitochondrial damage in the periphery and CNS of depressed patients and animal models of depression, the important question remains whether mitochondrial dysfunction is a cause or simply an accompanying feature of the behavioral phenotype. It seems unlikely that a single signaling pathway is responsible for the constellation of symptoms experienced by patients with depression. Nonetheless, it appears feasible that the symptoms of inflammation-associated depression are mediated, at least in part, by neuron-intrinsic effects related to mitochondrial bioenergetic dysfunction.Women have twice the incidence of depression than men . This mi2+ uptake (+)-dependent class III histone deacetylase involved in mitochondrial biogenesis and turnover, energy metabolism, and stress response, in cortical and hippocampal glutamatergic neurons resulted in depression-like behaviors in male but not in female mice  was significantly higher in the white matter and gray matter of female participants compared to males. However, two studies examining sex differences in cellular respiration of human platelets found no significant differences between males and females (However, research on sex differences in mitochondrial function has yielded mixed results. In rodents, female mice show increased ETC activity, ATP production, and fatty acid utilization, whereas mitochondria from male mice show increased ROS production, mitochondrial biogenesis, protein utilization, and Ca+ uptake . In resp+ uptake . Also, fale mice . In humaale mice . Activit females . ApproprThe emerging field of immunopsychiatry has contributed to our understanding on how alterations in the immune system might lead to depression in a subpopulation of patients. Even though not every depressed patient is inflamed, identifying and understanding inflammation-associated depression as a subtype of depression might help with the development of more effective therapeutic interventions. However, better treatment options can only be available after we gain a better understanding of the mechanisms by which inflammation leads to mood and behavioral alterations. Although the literature reviewed here is essentially correlative, the available studies point to an association between mitochondrial dysfunction in inflamed depression that deserves further investigation. Data from neurodegenerative and neuroinflammatory diseases show clearly that neuroinflammation impacts mitochondrial function at different levels. Conversely, DAMPs released by damaged mitochondria are potent inducers of inflammatory responses and might help to propagate neuroinflammation. This results in a potentially vicious cycle that can lead to bioenergetic deficits and impaired neuronal signaling specially in dopaminergic neurons that are under sustained oxidative stress and have high energy demands, ultimately leading to depressive symptoms. It seems intuitive that impaired mitochondrial bioenergetics underlie the symptoms of reduced incentive motivation, anergia, and motor slowing that are present in patients with inflamed depression. However, there are still significant knowledge gaps to be addressed before mitochondrial health can be efficiently targeted by new therapies to relieve symptoms of depression in patients with elevated levels of biomarkers of inflammation. Understanding the pathophysiology of depression is urgent, especially at this time in which the COVID-19 pandemic has affected more than 225 million people worldwide with many of the survivors presenting with long COVID-19. The cases of depression might drastically increase, not only because of the mental constraints imposed by lockdown, social distancing, personal and financial losses, but also because of perturbations of the immune-to-brain communication pathways caused by the infection and/or the neurotropic activity of the virus itself .AC drafted the manuscript. RD and CB-O edited and reviewed the manuscript. All authors approved the final version of the manuscript.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.


Clinical trials form the bedrock of evidence upon which clinical decision making is based. In multiple sclerosis (MS), the number of disease modifying therapies (DMTs) continues to expand with the number of clinical trials growing rapidly, especially over the past two decades. Phase III trials of DMTs are usually multi-centered, spanning many countries, and involve dozens of centers and hundreds of investigators. Meanwhile, efforts to improve racial and ethnic diversity in clinical trials in general in the United States have largely failed , 2. Justtour de force. Many stakeholders are beginning to re-examine who enters and leads clinical trials. Increasing scrutiny of the representativeness of people of color is therefore rightly gathering new attention by patients, investigators, and the general public as the science of MS rapidly advances.Current efforts to advance health equity via phase III clinical trials in MS appear inadequate. MS research is highly sensitive to the many structural inequities experienced across the U.S.A. Although clinical trials in MS have often been considered separate from broader social, cultural, and political trends, demands for equity in all aspects of American society are rightly becoming a bill AB 979 was passed to eliminate all-White boards of publicly traded companies headquartered in that state  and prior research funding from the National MS Society and Biogen, unrelated to this topic. She has received consulting fees from Biogen and Genentech, unrelated to this topic.


When viewed through the phenomenological lens of body-social as distinct from body-subject and body-object, findings demonstrated that the qualitative effectiveness of COPD-SGs is greatest on a collective basis. Qualitative research into the effectiveness of COPD-SGs offers more favourable results because phenomenological approaches can identify collective benefits that quantitative methods cannot. COPD-SGs should seek to maximise these collective benefits by rediscovering their cultural and artistic heritage within the national and global Arts in Health (AiH) movement, which has long emphasised the radical creative and healing power of group activity.Anecdotal experience and qualitative accounts suggest that singing groups, classes or choirs specifically for people with COPD (henceforth referred to as COPD-SGs) are effective in improving health. However, this is not reflected in the quantitative evidence. This meta-ethnography deployed phenomenological methods to explore this discrepancy. Analysis identified the phenomena of  You raise me up, so I can stand on mountainsYou raise me up, to walk on stormy seasI am strong, when I am on your shoulders1You raise me up, to more than I can beAcross cultures and societies worldwide, music expresses what it means and how it feels to be human. Everyone with functioning vocal chords can create and modify rhythm, pitch and tone and so the human voice is an instrument which even the most breathless of individuals can use together.Chronic obstructive pulmonary disease (COPD) is a progressive lung condition leading to life-limiting breathlessness and disability and to complex health and care needs . It is abeing and the body-social that enables individuals to transcend the isolation and disempowerment of their illness. Our assertion that the qualitative benefits of COPD-SGs operate primarily on a collective or social level will be valuable to clinicians and musicians alike in informing both the commissioning and delivery of COPD-SG activities.Qualitative research into lung disease increasingly employs phenomenological methods as a means of engaging not only with the physiological or psychological aspects of life with chronic illness but also with how breathlessness affects more fundamental questions of human embodiment and interrelatedness . This meWithin the artistic community, the effectiveness of improving collective wellbeing and health by using music to strengthen and empower communities has long been acknowledged . In its Despite the increasing levels of collaboration, partnership and innovation within this field, COPD-SGs  must nevertheless be distinguished from music therapy and from the arts psychotherapies and other arts-based medical treatments in general. The arts psychotherapies, like most forms of medical treatment, are individually task-orientated in its aim to treat symptoms, improve wellbeing, promote coping and target behaviour change. AiH, MiH and COPD-SGs, by contrast, are collaborative and process-driven, aiming foremost to generate a genuine and meaningful artistic experience and only as a by-product of that artistic experience to elicit wellbeing benefits. Whereas the arts psychotherapies are delivered by allied health practitioners working within the boundaries and structures of their profession, AiH, MiH and COPD-SG activities are facilitated by practising artists whose creative expertise and freedom from healthcare conventions enables mutuality, collaboration and co-creation with group members.Four recently-published literature reviews examining the evidence informing COPD-SGs have focused specifically upon COPD-SG outcomes for individuals. Each of these  found thEvidence of the effect of COPD-SGs on mental health and health-related quality of life varied in accordance with the measures used. In relation to all benefits of COPD-SGs, the qualitative data also offered stronger evidence than the quantitative. The experience of chronic breathlessness affects cognition, mood, emotion, coping and lifestyle in more complex and nuanced ways than structured clinical questionnaires can capture .None of these four reviews addressed the problem from which this meta-ethnography began: the disparity between the relatively equivocal quantitative data and the strong, mainly anecdotal qualitative benefits. The empiricism upon which quantitative research is based relies upon sensory observations, and much of the value of singing, music and the arts rests upon its subjective capacity to influence humans aesthetically, emotionally and spiritually .Phenomenology, as propounded by When approached phenomenologically, breathlessness generally appears the most distressing and disabling feature of chronic lung disease . Furtherbody-subject or lived body of first-person experience as distinct yet inseparable from the body-object of the medical gaze. For people living with long-term medical conditions, however, the experience of bodily impairment and reliance upon medical care can confound this dichotomy, compelling the individuals in question to engage with their bodies simultaneously as both a passive object of scrutiny and care and as an autonomous subject in possession of consciousness and agency  and In-der-Welt-sein (being in the world) as essential components of Dasein, being as shaped by human relatedness to and articulation with the world. The complexity of communal, collective or social ways of being a body are further developed by intercorporeity, or of individual human perceptions of their own existence as being interdependent upon those of others.The concept of the body as both individual and a communal, collective or social entity – the body-social – has its roots both beyond and within phenomenology. The concept has assisted anthropologists to challenge or reject the existence or nd other . By intrbody-social as a companion to the body-subject and body-object, we lay no claim to ontological innovation. Instead, we argue that the more conventional body-subject/body-object dichotomy of phenomenological health research  at Canterbury Christ Church University, UK , 2018, oWe began our search for relevant ‘grey literature’ from the websites of the SdHRC, SfBRG and MRINZ, exploring material provided and suggested by individuals associated with each research centre, and undertaking Google searches to investigate further questions arising. From the SdHRC, this led to the inclusion of the two evaluation reports , 2017 upbeing, and of how COPD-SGs affected individual and collective understandings of their bodies, featured predominantly throughout the literature this meta-ethnography reviewed.Within this study, data analysis followed broadly the framework for health meta-ethnography of phenomenological reduction: data analysis by the abstraction of experiences from experiencers, thereby identifying phenomena through establishing intersubjectivities that are purely transcendental in nature. As such, having identified the key findings from each study, this meta-ethnography sought to analyse emerging themes in isolation from the interpretations or conclusions placed upon it by their original authors. Themes within the data were then established by focusing upon their intersubjectivity, or upon identifying those phenomena that the researchers identified or interpreted as having been experienced within two of more of the COPD-SGs studied.Methodologically, Phenomenological research acknowledges that both the researcher and the researched share a common experience of being human . As suchbeing in their bodies  occurred on a communal or collective group-based basis. Analysis identified the phenomena of togetherness, uplifted-ness and involvement within the data. Each of these were framed within the concept of being to emphasise their intersubjective existence and reality within our phenomenological paradigm.Through according ontological parity to the togetherness in enabling them to transcend what they described as the grim experience of daily breathlessness. As individuals, participants valued their connection and commonality with one another. As groups, they preferred to identify as choirs rather than as support groups or as patient socials. Singing together, participants explained, unites people across social, cultural and ethnic backgrounds in ways that simply suffering from a common illness cannot  choir studied by the Medical Research Institute of New Zealand (MRINZ) in Wellington and the studies from the Sidney de Haan Research Centre (SdHRC) at Canterbury Christ Church University, UK , 2018, iLO study , COPD-SGAll studies found that participants enjoyed singing together , 2018. PAlongside, within and beyond this fun and enjoyment, participants also described the process of singing together in COPD-SGs as affecting them in ways that transcended their usual emotional repertoires or experience, which they struggled to describe . Studiesuplifted-ness) to the overcoming of social and cultural barriers which had enabled participants to transcend their lived experiences of illness and to sing together. They explain the potentially spiritual quality of this connectedness in terms of how singing in a group involves the coming together of different voices in harmony.uplifted-ness, arguing that participants are exhaling most effectively whilst singing, thereby suddenly receiving optimal capillary perfusion and brain activity. Nevertheless, uplifted-ness altered participants’ ways of thinking about themselves and the world around them, in some cases providing participants with a new outlook on life , and that the SfB model could not straightforwardly be transposed to a Ugandan context. When considered alongside the early anthropological antecedents to our conceptualisation of the body-social (COPD-SGs are increasingly becoming a global movement, and we recognise that, in drawing only from studies based in the UK and New Zealand, this meta-ethnography does not reflect this. As a theoretical tradition, phenomenology originates within the Western philosophical assumptions and debates around the existence and nature of the Self and the individuality of the human body . As a rey-social , this cubeing together, being uplifted and being involved, which operate on a communal or collective basis, rather than the conventional measures of impact on wellbeing or health interventions upon individuals. COPD-SGs are at their most effective on a communal or collective level because they approach the body as a social as well as an individual entity, endorsing Heidegger’s foundational aim of identifying the gap between phenomena and reality. The centrality of these communal or collective processes strengthens our argument that the body-social should be afforded parity of consideration with the body-subject and body-object in phenomenological research that seeks to engage with group-based health interventions.The phenomenological standpoint from which this meta-ethnography has developed concepts around the social and communal aspects of being and embodiment, has enabled it to focus upon the benefits of being as a collective phenomenon, and by identifying three phenomena of being together, being uplifted and being involved, this meta-ethnography offers findings distinct from previous reviews of the impact of COPD-SGs, which took the more empirically realist perspective of some of the organisations and services within which COPD-SGs operate. Not all COPD-SGs, and not all COPD-SG facilitators would identify themselves with the AiH movement or culture, sometimes preferring to describe themselves as healthcare interventions or social prescribing initiatives. Nevertheless, the AiH movement, from within which the concept of COPD-SGs and the mechanism of social prescribing originated, held a strongly collectively-focused ideology and ethos, seeking foremost to strengthen the wellbeing and health of communities by promoting collective identity, cohesion and consciousness as a means advocating social justice, involvement and activism. This meta-ethnography has demonstrated that, although the specific aims and techniques of COPD-SGs have developed ostensibly from a more individualised, behavioural or medicalised approach, and although COPD-SG members express no radical intent, the group-based heritage of the AiH movement remains nevertheless central to the power of COPD-SGs in improving wellbeing and health.Qualitative research into the wellbeing and health benefits of COPD-SGs offers more positive results because qualitative methods can discover what quantitative methods largely cannot. By identifying We argue, then, that this is a heritage and a tradition that COPD-SGs should embrace and draw from. COPD-SGs improve wellbeing largely through the cohesion and supportiveness of their groups. Those teaching, running or facilitating COPD-SG groups should consider how the structure of session and choice of activities might best support group members in bonding, socialising and developing a group identity together. COPD-SGs develop cohesion, supportiveness and identity most effectively when offered a meaningful level of ownership, self-determination or control over the delivery of the group. Those commissioning or managing COPD-SG services should consider a community choir model of service delivery to maximise their distinctiveness and value as groups, and to draw most fully from their heritage as facilitators of improved wellbeing. They will require some degree of autonomy from medical or rehabilitative services in order to delegate the necessary level of control to participants.


The microcirculation includes an invisible network of micro-vessels that are up to a few hundred microns in diameter. The microcirculation in each organ is largely responsible for end organ perfusion and the transfer of oxygen from red blood cells to the cells of the parenchyma to meet their energy requirements. In addition, the microcirculation drives a dynamic and demand-driven exchange of solutes between the intra-vascular and extra-vascular spaces, as well as the delivery of nutrients and blood-born humoral substances to tissues. Moreover, the microcirculation may exert these effects via the regulation of vascular tone.In many tissues, the structural or functional loss of micro-vessels characterizes disease progression and correlates with ultimate organ failure . Damage One of the mechanisms by which the microcirculation retains its integrity involves a continuous process of endothelial cell repair and replacement, as well as ongoing stimuli to facilitate and foster its expansion. The endogenous cellular repair system plays an important role in the maintenance of the endothelium, as well as parenchymal cells. This system includes bone marrow-derived blood-borne endothelial progenitor cells that continuously patrol the microcirculation to repair and replace injured endothelial cells and micro-vessels whenever and wherever encountered . Upon inHowever, these potent reparative systems can be injured or lost during development of systemic or local tissue disease, which may render them ineffective when a tissue requires reparative activities . This apCells focuses on the development and application of cell-based therapy for microvascular repair. The ubiquitous nature of microvascular damage as a fundamental mechanism of tissue injury is reflected in the variety of organs in which cell-based therapy has been attempted. The disease entities described in this Special Issue include renovascular disease associated with ischemic nephropathy in both humans [Being a fundamental pathogenic mechanism underlying tissue damage, microvascular repair has been positioned at the center of a number of therapeutic interventions. This Special Issue of h humans  and pigsh humans , lung inh humans , coronarh humans , and isch humans ,15. Noveh humans , are desh humans . Importah humans .Clearly, additional development is needed for the field of cell-based and cell-derived therapy, which is rapidly moving forward. For example, the use of stem cell-derived extracellular vesicles may alleviate some safety concerns associated with the delivery of live replicating cells , and theCells, will hopefully propel this field forward in the coming years.Overall, teamwork, scientific collaboration, and knowledge dissemination, as exemplified in the current Special Issue of


Cancers contains a series of articles presented by international leaders, focusing on the current clinical evidence supporting the standard of care and emerging therapeutic/prophylactic options for cancer-associated VTE during both active treatment and simultaneous/palliative care. Tailored approaches based on the use of individualized factors to stratify the thrombotic/bleeding risk in each individual patient are also discussed.Venous thromboembolism (VTE) is a compelling challenge across all phases of cancer care as it may result in treatment delays, impaired quality of life (QoL), and increased mortality . This SpThe increased risk of VTE in cancer is typically related to patient ,3, tumorKRAS in colorectal and lung cancer and IDH1 in brain cancer patients, the former being positively associated with TF upregulation, the latter being associated with hypermethylation of the F3 promoter of the TF gene leading to decreased TF expression and a decreased risk of VTE [ALK, ROS1, and JAK2, all participating in downstream signaling of inflammatory cytokines [Other tumor-related factors can concur to represent additional triggers of VTE in cancer patients. In this context, the advent of tumor genomic profiling has strongly contributed not only to a deeper comprehension of cancer biology, but also to the discovery of potential VTE risk genomic factors. The subject is addressed in the review by Leiva and colleagues discussing the potential mechanisms by which the tumor mutational status may influence thrombogenesis . Moleculk of VTE . Other tytokines , while tytokines . Knowledytokines .While many factors contribute to increase the individual thrombotic risk, some co-morbidities and/or chemotherapy-related side effects, such as renal or hepatic insufficiency and thrombocytopenia, can affect the efficacy and safety of anticoagulation, emphasizing the need for a careful evaluation of the risk/benefit assessment of anticoagulant prophylaxis. Hence, the availability of tailored approaches—based on the use of individualized factors to stratify the thrombotic/bleeding risk in each individual patient—undoubtedly represents a significant advance in the prevention of cancer-associated VTE. Several clinical decision models have been developed to guide the oncologist in thromboembolic risk assessment and targeted prophylaxis. The article by Mulder et al. addresses some of the controversies stemming from the translation of the guideline recommendations into clinical practice, discussing the performance of available risk assessment scores, and summarizing the findings of recent trials . From thThe state-of-the-art current guidelines on thromboprophylaxis in cancer patients is addressed in the reviews by Labianca et al.  and RossOne of the most important novel developments that can be found in the latest recommendations by expert societies is the endorsement of the use of edoxaban and rivaroxaban for VTE treatment/prophylaxis in cancer patients ,15. DireThe use of DOACs in VTE treatment and primary prevention in cancer patients is the focus of the review by Wojtukiewicz and coworkers . LMWH haOur digression on the topic of VTE risk stratification and antithrombotic prophylaxis continues with some examples focusing on some high-risk tumor types. The first of these reviews is that by Farge and colleagues  who addrFotiou et al.  and HohaFinally, Riondino et al.  and ZabrFrom the aforementioned data, it emerges that a large series of experimental and clinical data has given a tremendous impulse to disentangle the issue of VTE risk assessment in cancer, tracing new horizons for thromboprophylaxis in selected at-risk patients. A common need for new tools clearly emerges. As a consequence, clinical decision-making is rapidly moving from empiricism to customized healthcare and tailored therapy. Adjunctive clinical risk factors, biomolecular markers, and dynamic risk assessment could all ameliorate VTE prediction, while the introduction of novel computational analyses could help with gaining knowledge from available datasets to obtain accurate and precise personalized risk estimates.