The Emotional Well-Being and Economic Burden (EMOT-ECON) Research Network is one of six research networks funded by the National Institutes of Health (NIH) to advance research about emotional well-being (EWB), and the only one that focuses on addressing how economic burden due to disease or illness affects EWB. The network convened researchers, patients, patient advocates, health care providers and other stakeholders from across the US to discuss the significance of addressing the impact of the economic burden of disease on EWB, the complexity of this prevalent problem for patients and families, and the research gaps that still need to be studied to ultimately develop strategies to reduce the impact of economic burden of disease on EWB and health. Participants identified some important future areas of research as those investigating: (i) prevalent and relevant emotions for patients experiencing economic burden of disease and financial hardship, and how their broader outlook on life is impacted; (ii) constructs and contexts that influence whether the economic burden is stressful; (iii) strategies to deal and cope and their positive or negative effects on EWB and health; and (iv) multi-level and multi-stakeholder interventions to address economic factors , administrative burdens, education and training, and especially patients’ emotional as well as financial status. About 6Medical financial hardship is associated with worse mental and physical health, and leads to behaviors such as forgoing medical treatment and delaying health care that can be detrimental to health . Howeverexperiential features  and reflective features ”  Research Network was funded to spearhead research and develop new insights about the impact of economic burden of disease on emotional well-being, with the ultimate goal of developing the strategies needed to reduce such impact. It is one of six research networks funded by National Institutes of Health (NIH) agencies to advance research about emotional well-being. Recently, emotional well-being has been defined as “a multi-dimensional composite that encompasses how positive an individual feels generally and about life overall, including both e self)” . The eco2.2.1.strategies to deal or cope with the stressor, selected based on the emotion-and problem-focused coping behaviors identified by The four-hour virtual Strategic Planning Meeting included 13 invited participants from across the US including researchers, patient advocates, and health providers, plus EMOT-ECON investigators  and staff. It started with a summary of existing literature and presentation of a conceptual framework to guide research of the network adapted from an established stress and coping theory  Figure . This fr2.2.The in-person Scientific Meeting was a full day meeting with a total of 29 participants from academic and other institutions across the US including patients and patient advocates, health care providers, representatives from financial and media agencies, and researchers with expertise in psychology, sociology, economics, medicine, and health services research. The meeting included two sets of discussions with one moderator and 5–6 participants in each of 5 roundtables. Each set of discussions lasted about 40 min and the major themes from each roundtable were then shared with the larger group. Participants used sticky notes to write their answers to the posed discussion questions. These were collected by the moderators to guide the discussions and the summary reports to the larger group. All notes were subsequently transcribed. Summary reports were recorded.strategies used to deal or cope when facing different aspects of financial hardship, as well as their potential positive and negative effects on patients (direct effects), and caregivers, families, and others (indirect effects). For the second roundtable, attendees were asked to discuss potential interventions for primary, secondary and tertiary prevention. Primary prevention interventions were described as those that may be implemented to prevent the economic burden of disease from becoming a stressor. Secondary prevention interventions were described as those that may be implemented to identify and support patients who experience financial hardship to prevent an impact of financial hardship on emotional well-being. Finally, tertiary prevention interventions were described as those that may be implemented to manage poor emotional well-being resulting from economic burden of disease to avoid exacerbations and complications such as, for example, clinical depression.For the first roundtable, participants were asked to discuss the different types of 3.3.1.Participants discussed limitations in the definition and measurement of both emotional well-being and financial hardship. For patients who experience medical financial hardship, unique and important elements that may not be appropriately assessed in existing measures of emotional well-being include the ability to get needed care and the ability to remain productive in day-to-day or work-related activities. With respect to economic burden, attendees proposed measuring a different construct. Acknowledging existing measures of overall financial well-being, they discussed measuring medical financial well-being rather than hardship, and then identifying protective factors that may preserve such financial well-being, which would benefit the field by shifting the focus on primary prevention. Similarly, participants noted that current measures of financial hardship relate to defined limited time points, e.g., over the past week or month, and miss the measurement of longer-term or chronic financial hardship, which may have different impacts on emotional well-being and health.3.2.uncertainty and unpredictability, compared to other financial stressors that may be more predictable, such as regular bills and expenses. The following characterize the economic burden of diseases:Before discussing the mechanisms by which the economic burden of disease affects patients’ emotional well-being, participants discussed at length what influences whether the economic burden of disease becomes a stressor. First, participants discussed a hallmark of this stressor, the extreme Unknown amounts of out-of-pocket expenses for medical care, even when patients are insured;Unknown timing of medical bills, including when patients are billed and when they should pay the bill;Unknown consequences of being unable to pay medical bills and worry about being unable to access needed treatment.It was recognized that patients and their families may have varying baseline financial skills or self-efficacy to problem-solve when faced by these kinds of uncertainty.difficulty of dealing with financial issues as a specific and related stressor. Patients may have difficult and stressful interactions with insurance companies and health care billing offices, and may face the threat of having medical debt turned to collection agencies. These interactions add stress even at low levels of economic burden.Second, attendees identified the Participants then discussed how research should investigate the extent to which the economic burden of disease is perceived as a stressor across life circumstances. For example, this may depend on when the disease occurs during the lifespan, levels of available family or other support, cultural belief systems, socioeconomic status, or other social determinants of health. Given these varying circumstances, there may be a differential impact on the experiential and reflective components of emotional well-being described above . SimilarWith respect to mechanisms by which the economic burden of disease affects emotional well-being, participants discussed the role of what people do to deal or cope with the burden. First, upon reviewing the strategies listed in the conceptual framework, it was recognized that some of them have positive or negative effects on emotional well-being and health. For example, a problem-focused strategy cancer patients commonly adopt is to forgo medical care or to skip prescribed medications to reduce costs . This maLastly, participants discussed valuable areas of research to understand factors that could moderate the impact of economic burden of disease on emotional well-being. In particular, those discussed were: (i) comfort with uncertainty, (ii) literacy  and the ability to understand costs and manage other personal economic challenges; (iii) resilience; (iv) personal empowerment in interacting with different medical and non-medical professionals to navigate financial hardship; (v) available resources such as support or insurance; and (vi) living context that may be characterized by existing policies or type of health care system, i.e., for example a system of universal health care coverage.3.3.Considering the stress caused by uncertainty, unpredictability, and dealing with financial issues, participants discussed potential benefits of interventions to improve knowledge of costs, such as financial and/or insurance education interventions. For example, financial counseling/navigation interventions are designed to link patients to needed resources, but could be extended to include efforts to inform patients about monetary costs or time off work, and even guide patients to choose care based on cost information, if appropriate. Entities providing such services could be within health care system or outside: for example, financial and/or insurance education programs may pair insurance representatives with patients to help them choose the “right” insurance, guide them through open enrollment processes, evaluate if supplemental insurance is needed, or simply help them understand what their insurance covers. Participants discussed ongoing projects where patients are paired with a financial counselor from a non-profit consumer education and training service group who help guide patients manage expenses while on treatment .Participants considered whether individual-level interventions alone would be effective in reducing the impact of economic burden of disease on emotional well-being. Specifically, there was some discussion on whether stress reduction, coping-based interventions, or family interventions would be effective. Overall, it was acknowledged that financial hardship cannot be addressed solely at the individual level. Attendees considered what kind of studies could be done to inform healthcare policies to prevent economic burden of disease. For example, studies could compare the level of economic burden or financial hardship across states or other geographic areas with different drug pricing policies or health care or insurance market dominance.3.4.Based on the discussions, the network’s conceptual framework was updated as shown in 4.4.1.4.2.Participants discussed interventions at society or community, policy, and health care system levels across the three prevention approaches . Discussions for tertiary prevention to manage poor emotional well-being resulting from economic burden of disease and prevent exacerbations and complications reflected on the effects of economic burden and the strategies to deal and cope with this burden reported in 5.Researchers, patients, health care providers, patient advocates, and other stakeholders, bring unique perspectives to the task of understanding the impact the economic burden of disease on emotional well-being and ultimately on health. This cross-disciplinary lens made for unusually energizing and creative discussions at the Strategic Planning and Scientific meetings of the EMOT-ECON network, attesting to the unique value and power of this approach. Overall, although not an exhaustive list, participants identified some important future areas of research, which included: (i) aspects of emotional well-being relevant to patients experiencing economic burden of disease and financial hardship, both in terms of what are prevalent and relevant emotions, and how the broader outlook on life is impacted; (ii) constructs and contexts that may influence, or protect from, perceiving the economic burden as stressful; (iii) ways in which patients deal or cope with the medical financial hardship across different contexts and populations with positive or negative effects on emotional well-being and health; and (iv) interventions at multiple levels and from multiple stakeholders that address economic factors , administrative burdens, education and training, and especially patient’s emotional as well as financial status.Discussions at these EMOT-ECON meetings and the updated framework align with current research on financial hardship. For example, recent research has started to recognize the complexity of such hardship which is not only due to high costs of care or reduced ability to work and earn an income, but to uncertainty and the difficulty of dealing with financial issues. Cancer patients in The strategies identified in our meetings to deal and cope with the economic burden of disease build on those identified in previous literature . SeveralParticipants highlighted how interventions to prevent or mitigate financial hardship are not limited to providing financial support either by reducing costs or providing financial navigators or counseling. Some of these interventions have been or are currently being tested , and wilIn summary, discussions at the EMOT-ECON network meetings highlighted the significance of addressing the impact of the economic burden of disease on emotional well-being and beyond, the complexity of this prevalent problem for patients and families, and the research gaps that still need to be studied. The EMOT-ECON network will support researchers who tackle these research gaps to advance understanding of both the economic burden of disease and emotional well-being, and help build the knowledge base to ultimately develop strategies to reduce the impact of economic burden of disease on the emotional well-being, and ultimately the health, of patients and their loved ones.MPi and MM developed the concept and obtained funding for the EMOT-ECON network. MPi wrote the manuscript. MM and ML contributed critical revisions to the first draft of the manuscript. All authors contributed to organization, conduct of the EMOT-ECON meetings, manuscript revisions, read, and approved the submitted version.This study was funded by the National Center for Complementary and Integrative Health (NCCIH), the Office of Behavior and Social Sciences Research (OBSSR), the Office of Disease Prevention and National Institutes of Health Office of the Director (U24AT011310).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.


Introduction: As the world continues to urbanize, particularly in low- and middle-income countries, understanding the barriers and effective interventions to improve urban immunization equity is critical to achieving both Immunization Agenda 2030 targets and the Sustainable Development Goals. Approximately 25 million children missed one or more doses of the diphtheria, tetanus and pertussis (DTP3) vaccine in 2021 and it is estimated that close to 30% of the world’s children missing the first dose of DTP, known as zero-dose, live in urban and peri-urban settings. Methods: The aim of this research is to improve understanding of urban immunization equity through a qualitative review of mixed method studies, urban immunization strategies and funding proposals across more than 70 urban areas developed between 2016 and 2020, supported by Gavi, the Vaccine Alliance. These research studies and strategies created a body of evidence regarding the barriers to vaccination in urban settings and potential interventions relevant to low- and middle-income countries (LMICs) with a focus on the vaccination of urban poor, populations of concern and residents of informal settlements. Through the document review we identified common challenges to achieving equitable coverage in urban areas and mapped proposed interventions. Results: We identified 70 documents as part of the review and categorized results across (1) social determinants of health, (2) immunization service-delivery barriers and (3) quality of services. Barriers and solutions identified in the documents were categorized in these thematic areas, drawing information from results in more than 21 countries. Conclusion: Populations of concern such as migrants, refugees, residents of informal settlements and the urban poor face barriers to accessing care which include poor availability and quality of service. Example solutions proposed to these challenges include tailored delivery strategies, improved use of digital data collection and child-friendly services. More research is required on the efficacy of the proposed interventions identified and on gender-specific dynamics in urban poor areas affecting equitable immunization coverage. As of 2019, an estimated 55% of the world’s population lives in urban areas and this percentage is expected to increase to 68% by 2050 . AdditioGavi, the Vaccine Alliance is a global financing entity for vaccination with a strategic priority on improving the equity of vaccination to reach zero-dose children. The Alliance includes the World Health Organization (WHO), UNICEF, the World Bank, the Bill and Melinda Gates Foundation (BMGF), the US Centers for Disease Control (CDC), implementing country governments and civil societies . To infoThe research plan and coding framework were developed in consultation with the global Urban Immunization (UI) working group. The UI working group was created by key immunization partners, including UNICEF and WHO, to create awareness about inequities in urban areas and support development of strategies to meet specific immunization needs of marginalized communities.We used a qualitative content-analysis methodology to analyze results across country urban immunization diagnostic studies, presentations, strategic documents and proposals. Diagnostic studies were mixed methods, including qualitative and quantitative data on urban immunization. Strategy documents were developed by technical partners and Ministries of Health to plan and cost interventions to address identified barriers to immunization coverage. The investment proposals were funding applications for Gavi support from Ministries of Health. Proposals which included urban immunization were eligible in the review as they presented data on urban equity and interventions designed to improve urban immunization. In this research, we followed a three-step content analysis process proposed by Elo and Kyngas (2008): 1. Preparation, 2. Organizing, and 3. Reporting .In the preparation phase, we sourced and identified the prospective documents for analysis. To source documents, a request for urban diagnostics, strategies, and proposals was shared with all country focal points at Gavi, the Vaccine Alliance in 2019 and early 2020. All shared documents were organized into a digital Sharepoint library inclusive of government, technical assistance, and internal proposals. All documents were reviewed against the criteria in Among the 70 documents included in the analysis, there were 30 diagnostic studies, 1 study presentation, 16 strategies, 6 strategy presentations, 14 funding proposals, 2 application review documents, and a meeting report. Forty-six of the documents were dated 2018 and 2019, with 10 documents having an unknown date. The source of the data in the documents varied, with some studies engaging directly with marginalized communities through Focus Group Discussions (FGDs) and others drawing inferences from existing data sets. All documents focused on the urban context.The studies and strategies across the urban immunization programs used both quantitative and qualitative methodologies to identify and measure immunization barriers. There are four data points or sources in the studies: (1) assessing health facilities and mapping (quantitative data), (2) caregiver exit interviews , (3) interviews with the frontline workers and caregivers , and (4) solutions and recommendations for improvement. Strategies detailed prioritized interventions for improving immunization equity in urban areas.The urban immunization strategies and financing proposals included information on barriers to vaccination and proposed interventions. We identified and included reports and costed strategies across 20 Gavi-eligible countries to understand the specific challenges to equitable immunization coverage in selected cities. To analyze the findings, we used a thematic analysis derived from the urban immunization toolkit organized by (1) the social and economic determinants of health, (2) immunization service delivery, and (3) the quality of service.The diagnostic reports and country strategies presented evidence of inequalities in service delivery to populations of concern, such as migrants, refugees, internally displaced persons, and homeless and poor populations in urban contexts such as residents of informal settlements. Inequities included availability and proximity to service, discrimination, and security. Populations of concern may have to travel far for services and may not be included in microplanning for outreaches. In a study in Somalia on three urban centers, IDP caregivers reported that they were not part of the immunization campaign, even though they expressed their desire to have access to immunization services . ProximiMarginalized communities, such as refugees and populations with insecure housing face additional barriers to reaching services, including the lack of residency cards for publicly supported services and language barriers. Refugees were one group which experienced discrimination and inequality in accessing immunization services for marginalized populations in urban settings. In Uganda, refugees reported being skipped in the waiting line and charged additional fees. Security concerns also present a unique challenge for health workers and caregivers alike. In Cite-Soleil, Haiti, 18% cited fear of insecurity as a reason for incomplete vaccination, “zero dose cases in slums are mostly due to vaccinators’ reluctance to visit security risk areas” .Solutions aimed to tailor delivery and demand strategies to reach marginalized urban residents through community engagement and improved forecasting of vaccines to populations of concern. Recommendations included in country diagnostics and strategy reports are summarized in Service-delivery barriers facing urban communities related to the provision, distribution, and quality of the major inputs of immunization services such as (1) health workers , (2) immunization site location, accessibility, and hours , (3) functional cold chain equipment, and (4) vaccine availability due to poor population data, last mile stock visibility and forecasting, and the incorrect application of open-vial policy. Moreover, there were significant governance issues between the government ministries, and private providers. A summary of common challenges across these areas is provided in Insufficient sites for immunization services may result in long travel times. In Kabul, 69% of the population takes over one hour to reach a health facility . In UganKenya, Ghana, Haiti, and Uganda’s urban assessments noted stock-outs as a barrier to vaccination ,13,14. IPublic service-delivery provision is not expanding at the rate of the rapid population growth in urban areas and results in many of the issues described above such as stock-outs and long wait times. The gap in public service delivery is often filled by private and faith-based facilities. This creates a challenge in coordinating, managing, and maintaining immunization service quality. In Nepal, the reasons for choosing the facility by clients included proximity of residence (70%) and perceived better-quality services (37.5%) . In KyrgThe aims of solutions to improve health planning in urban areas included the improved collection and use of data, improved vaccine forecasting, enhanced political commitment and financing for human resources and service delivery. The strategies identified the need to engage private healthcare providers, as there are more private providers in urban areas. This included a common recommendation to identify a model for immunization delivery between the government and private providers. Proposed models include contracted service delivery, referral from private to public services to immunization, and the need to include healthcare workers of private health facilities in immunization trainings. The recommendations and proposed interventions for country strategies are available in The main demand-side barriers in urban areas ranged from lack of information—poor communication on the importance of vaccination, location, and timing of sessions—to stronger deterrents, including misinformation and poor treatment by health workers. Further, the lack of information on the demographics of beneficiaries for tailored communications, attention to child-friendly services, and models of community mobilization were largely absent from program plans and diagnostics.Costs related to seeking immunization services in urban areas included charges for services, commodities , transport, and lost wages. Despite existing policies protecting caregivers from costs for a free, public service, illegal charges were reported in numerous diagnostic studies. In Angola, a supervisor noted the constraint for “the population are the illegal charges, both for the vaccination cards and the vaccines” . SimilarLong wait times for immunization sessions were cited across cities, ranging from only 30 min (Kenya) to 5 h (Haiti) ,14. SympRespondents in Ghana cited being discriminated against for not having nice clothes to wear to the facility and 44% of respondents in the study noted the negative attitude of the provider as a discouraging factor . In SierWorking parents, particularly those employed in the informal sector, faced a choice to vaccinate or lose income required for daily subsistence. In Bangladesh, 17% of caregiver respondents reported being “too busy” to complete the full vaccination schedule . In SomaRecommendations and proposed strategies ranged from healthcare worker interpersonal training to the hiring of outreach workers from marginalized populations to improve engagement. Efforts to tailor the service-delivery model to working and busy caregivers included interventions such as a dedicated vaccination line and after-hours vaccination. The use of mobile phone networks to share information and vaccination reminders was proposed in more than seven countries. Child-friendly improvements to clinics was a common intervention to improve the quality of care and immunization experience. The recommendations and proposed interventions for country strategies are available in The strengths of this study draw from the number of documents reviewed across a broad range of countries in different regions, encompassing more than 70 urban centers. Despite the variance in socio-economic realities between the settings, common challenges and solutions emerged which may be the starting point and reference for the design of effective urban immunization programs. Although several of the barriers and solutions identified could be valid across rural and urban populations, the findings were in line with the Gavi Urban Immunization Programming Guidance and the Equity Reference Group discussion paper on tackling immunization inequities in urban contexts, which outlines the following issues as unique to urban areas or exacerbated due to the urban context. In summary, these include the insufficient availability of public facilities, high population density and insufficient disaggregated data, seeking of healthcare across public and private facilities, a lack of formal addresses, insecurity, highly mobile populations, caregivers’ demands on time due to employment, complex community structures and a diverse population, requiring a tailoring of activities ,20. ThisThe findings for identified challenges due to social and economic determinants of health, including residents of informal settlements and migrants, are consistent with the literature, as documented in the systematic review by Crocker-Buque et al.  However,Results showed challenges related to the growth of private sector services and costs to caregivers, including the loss of income . While tChallenges to immunization equity in the urban context largely link to appropriate health planning and the design of inclusive and accessible health services for populations of concern and working caregivers ,24,25. TThe poor quality of services, rooted in the planning, financing, and execution of immunization sessions, in areas of rapid urban growth likely results in poor demand for immunization services in many urban poor areas. The specific causes of reduced demand linked to service delivery in urban poor areas are related to quality of care and include stock-outs, poor interaction with health workers, wait time, constrained hours, and cost. The recommendations for improvements in these areas include investment and prioritization, bringing children to already existing services in under-resourced areas, improving healthworker interaction and rebuilding the reputation of the immunization programs. These are consistent with the review by Oyo and Nelson et al. ,30.In some settings, there was a refusal of care to populations of concern such as migrants. The review showed health workers were not well represented in the studies and further evidence is needed to understand their work environment and challenges in providing care in urban areas and biases in serving populations of concern. The issues with quality of health worker interaction were consistent across the majority of studies and recommendations. However, as noted by Suphanchaimat, there are also constraints in resources available to health workers and incongruence of legislation and professional norms and ethics in provision of service to migrants .Although the review presents new evidence to contribute to the evidence of urban immunization equity, the study is limited due to non-standardization of the methods in the documents included in the review. There was no uniform method to the 30 studies reviewing barriers and challenges to immunization equity which limited the analysis to a documentary review. Further, the availability of data from key areas such as gender was limited as the diagnostic tools used for most of the urban immunization studies sourced for this review did not include a robust methodology for gender analysis. As the documents included in the analysis were developed at the planning and strategy-development phase, the results only show proposed solutions and interventions, without data on which interventions may be effective. Finally, the analysis does not compare the urban and rural experience due to approach and similar available documentation specific to rural environments. The research identified areas for further inquiry. Additional gender research is needed to include complex issues such as working parents, the link between health services and daycare, building on recent analysis in this space ,33. The The combination of insufficient service delivery for immunization and poor quality of care, particularly for populations of concern shows the importance of tailored health investments and strategies in cities and provides evidence to explain the large number of zero-dose and under immunized children residing in urban contexts. The recommendations compiled through the review and developed uniquely by each country in their strategy development represent an important starting point for urban immunization programming to overcome barriers commonly identified in the urban context. This research can help inform and improve guidance in the development of urban immunization strategies and presents additional research priorities needed to evaluate suggested interventions in addressing urban equity. A research agenda based on the gaps identified in the review and input from the urban immunization working group is presented in


Ischemic stroke is caused by a reduction in blood flow to the brain and is a major cause of mortality and disability worldwide. Cerebral ischemia initiates a complex cascade of events at genomic, molecular, and cellular levels, and inflammation is important in this cascade, both in the central nervous system (CNS) and the periphery ,2,3. FurInflammation is an important part of stroke pathophysiology, especially in the context of reperfusion. Several studies have shown that a nonspecific systemic inflammatory response occurs after both ischemic and hemorrhagic stroke, proving that inflammatory mechanisms intrinsic to the brain and the blood are among the important mediators of focal cerebral injury. The immune system is actively involved in the pathogenesis of acute brain damage through some events, such as leukocyte and monocyte infiltration into the brain, the activation of resident cells, including microglia, astrocytes, and endothelial cells, and several high serum levels.Few studies have examined the relationship between inflammatory biomarker blood levels, cardioembolic stroke subtype, and neurological deficit. A study by our own  group exAnimal models of focal ischemia induced by middle cerebral artery occlusion (MCAO) provide evidence for most of the cellular inflammatory responses in stroke.In this Special Issue of the International of Molecular Sciences (IJMS), some authors reviewed the role of inflammatory cytokines in the pathogenesis of ischemic neuronal damage. We will also review the involvement of microglial cells, which are the major resident immune cells in CNS, and play a critical role in the immune response to a variety of events, including infection, trauma, stroke, and neurodegeneration. Among the various types of circulating leukocytes, neutrophils are generally the first leukocyte subtype recruited to the ischemic brain, and we will review their role in ischemic stroke pathogenesis. The inflammatory responses of the brain to post-ischemia are characterized by the involvement of different subtypes of T lymphocytes, which contribute to the pathogenesis of stroke-induced microvascular dysfunction and tissue damage. The authors also reviewed the role of T lymphocytes and their subsets. T-cells can be separated into three major groups based on function, as follows: cytotoxic T-cells (CD8+), helper T-cells , and regulatory T-cells (Tregs). We will review the literature on the available data concerning their involvement in ischemic stroke pathogenesis. We will also review the role of inflammatory mediators in a particular subtype of ischemic stroke, such as cardioembolic and atherosclerotic ones.In the first article of this Special Issue, Carandina et al.  targetedIn recent years, starting from the bidirectional relationship between autonomic nervous system (ANS) dysfunction and acute ischemic stroke (AIS), researchers have identified prognostic factors for risk stratification, the prognosis of mid-term outcomes, and the response to recanalization therapy. Impaired autonomic function, characterized by a predominance of sympathetic activity, is common in patients with acute ischemic stroke. Some of the variables used, such as autonomic activity markers , have beIn the second article, Tuttolomondo et al.  reviewedIn the third article, Di Raimondo et al. reviewed the role of regular physical activity in neuroprotection against acute brain ischemia .Neurotrophins such as brain-derived neurotrophic factor (BDNF), which is widely produced throughout the brain but also in distant tissues, such as muscles, has demonstrated regenerative properties and the potential to restore damaged neural tissue. Neurotrophins play a significant role in protecting and recovering function following neurological diseases such as ischemic stroke or traumatic brain injury. Unfortunately, the efficacy of the exogenous administration of these neurotrophins is limited by rapid degradation with subsequent poor half-life and a lack of blood–brain barrier permeability. Regular exercise seems to be a therapeutic approach that can induce the activation of several pathways related to the release of neurotrophins. Furthermore, exercise reduces the infarct volume in the ischemic brain and ameliorates motor function in animal models, increasing astrocyte proliferation, inducing angiogenesis, and reducing neuronal apoptosis and oxidative stress. One of the most critical issues is to identify the relationship between neurotrophins and myokines, newly discovered skeletal muscle-derived factors released during and after exercise, which can exert several biological functions. Various myokines  have recently been shown to protect against neuronal injury in cerebral ischemia models, suggesting that these substances may influence the degree of neuronal damage in part via inhibiting inflammatory signaling pathways. Thus, the authors evaluated the main experimental data available to date on the neuroprotective and anti-ischemic role of regular exercise, also analyzing the possible role played by neurotrophins and myokines.IL-6, BDNF, COX2, CYPC19, and GPIIIa, could be associated with stroke outcome and recovery. Recent GWAS studies pointed to the variant in genes PATJ and LOC as new genetic markers of long-term outcomes. The epigenetic regulation of immune response in stroke is also important, with mechanisms of histone modifications, DNA methylation, and the activity of non-coding RNAs. These complex processes change from the acute phase over the repair to establish homeostasis or provoke exaggerated reactions and death. The pharmacogenetics and pharmacogenomics of stroke cures might also be evaluated in the context of immuno-inflammation and brain plasticity. Potential novel genetic treatment modalities are challenged but they are still in the early phase of investigation.Further, Nikolic et al.  evaluateFinally, Maida et al. ,14 revieImmune mediators are the origin of signals with a proinflammatory position that can boost the cells in the brain and promote the penetration of numerous inflammatory cytotypes  within the area affected by ischemia; this process is responsible for further ischemic damage of the brain. This inflammatory process seems to involve both the cerebral tissue and the whole organism in cardioembolic stroke, the stroke subtype that is associated with more severe brain damage and a consequent worse outcome  ,20,21,22


Circulatory shock, defined as a life-threatening, generalized form of acute circulatory failure in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, remains a major contributor to morbidity and mortality in critically ill patients. Hemodynamic management traditionally focuses on increasing global oxygen supply, most commonly through optimization of stroke volume and cardiac output. While early guidelines have mostly recommended to maximally utilize the oxygen-carrying capacity of the blood, recent studies have put oxygenation targets in the spotlight in the management of critically ill patients in circulatory shock. Several aspects underline the importance of thoughtful and individualized (re-)consideration of oxygenation targets . First, The discussion of oxygenation targets inevitably raises the question of considering global versus tissue-centered resuscitation goals. While current practice mostly targets global delivery of oxygen, emerging techniques to quantify tissue perfusion and oxygenation place the direct targeting of determinants of tissue oxygenation within reach of the clinician. Tissue perfusion, which essentially describes the movement of hemoglobin carriers through the capillaries, or, in other words, the perfusion of the tissue with red blood cells , dependsThe thematic collection “Tissue oxygenation: how to measure, how much to target” invites authors to focus on diagnostic and therapeutic aspects of a direct view on the determinants of tissue oxygenation. The aim is to not only contribute to a tissue-centric perception of the concept of oxygen delivery and extraction, but also to set the stage for taking the next step to improve the management in critically ill patients suffering from circulatory shock.


Luminescent solar concentrators (LSCs) are all-photonic,semitransparentsolar devices with great potential in the emerging fields of building-integratedphotovoltaics and agrivoltaics. Over the past decade, particularlywith the advent of quantum dot (QD) LSCs, tremendous progress hasbeen made in terms of photovoltaic efficiency and device size by increasingsolar spectral coverage and suppressing reabsorption losses. Despitethese advances in LSC design, the effects of environmental conditionssuch as rain, dust, and dirt deposits, which are ubiquitous in bothurban and agricultural environments, on LSC performance have beenlargely overlooked. Here, we address these issues by systematicallyinvestigating the environmental effects on the solar harvesting andwaveguiding capability of state-of-the-art QD-LSCs, namely, the presenceof airborne pollutants (dust), water droplets, and dried deposits.Our results show that dust is unexpectedly insignificant for the waveguidingof the concentrated luminescence and only reduces the LSC efficiencythrough a shadowing effect when deposited on the outer surface, whiledust accumulation on the inner LSC side increases the output powerdue to backscattering of transmitted sunlight. Water droplets, onthe other hand, do not dim the incident sunlight, but are detrimentalto waveguiding by forming an optical interface with the LSC. Finally,dried deposits, which mimic the evaporation residues of heavy rainor humidity, have the worst effect of all, combining shading and waveguidelosses. These results are relevant for the design of application-specificsurface functionalization/protection strategies real LSC modules. A compelling exampleof this is the effect of various types of dry or wet deposits on anLSC waveguide, which in addition to reducing the amount of solar lightthat can reach the waveguide and be converted into useful guided PL—asit commonly occurs for direct charge generation in conventional PVmodules54—can also affect the transportof light energy to the device edges by disrupting the waveguidingby total internal reflection.After a few decades of apparent waning interest,the advent ofcolloidal semiconductor quantum dots (QDs) as reabsorption-free NIRLSC emitters nearly a decade ago has revived research in the field,In this work, we aim to contributeto this endeavor by investigatingthe impact on LSC performance of probably the most common environmentalfactors that could occur in urban or agricultural contexts, namely,dust accumulation, wetting by water droplets, or the presence of continuouswet layers on the external or internal surfaces of the panels, aswell as the influence of dried residues left after evaporation ofwater, as could occur after rainfall on buildings or irrigation ingreenhouses. The quantitative performance evaluation indicated thatthe accumulation of dust on the LSC outer surface reduces the LSCefficiency by a shadowing effect that lowers the intensity of sunlightentering the panel  but does not detriment the waveguiding behavior, leadingto no losses of propagating luminescence. On the other hand, the continuousoptical interface between the surface of a polyacrylate LSC and waterdroplets was found to be very detrimental to light propagation. Finally,the accumulation of dried residues combined the detrimental effectsof dust and liquid deposits, causing both shadowing of the LSC andreduced waveguiding. These results provide some clear guidelines forrationalizing the future treatments on LSC surfaced designed to preservetheir performances.2, thickness = 7.5 mm, 70% transmittance between400 and 900 nm) containing CuInS2/ZnS QDs (0.1 wt %) werefabricated by industrial cell casting of methyl methacrylate monomersusing Lauroyl peroxide as thermal radical initiator (500 ppm).38 The QDs were prepared according to the syntheticprotocol described in the Methods section of Supporting Information, and their size was tuned to provide maximum spectralcoverage while matching the transparency window of the LSC, whichis determined by the absorption onset of the QDs (short wavelengthlimit) and the first C–H absorption overtone of the PMMA at∼915 nm (long wavelength limit). The absorption and PL spectraof the LSC are shown in PL = 65%.Large-area poly(methyl methacrylate)(PMMA) LSC waveguides (20× 20 cm2 QDs28 (details of the simulation procedure are reported in theMethods section in the Supporting Information).The suppression of self-absorption by the QDs and the high opticalquality of the PMMA waveguide led to an essentially complete absenceof reabsorption and scattering losses, as confirmed by the inset of waveguiding mode, targeted the light-guidingperformance of an LSC and consisted of illuminating the terminal partof an LSC, which was kept clean, with a calibrated solar simulator,while the majority of the device surface was covered with increasingamounts of deposits  and kept in darkness bya shadow mask.Having verified the quality of our testbed QD-LSC device,we proceededto investigate the effect of different types of deposit in order toreproduce real operating conditions. In these experiments, we focusedon the two processes that most determine the performance of LSCs,sunlight harvesting, and light propagation. As shown schematicallyin illumination mode (2) and was found to correlate linearly with the mass amountof deposited material, suggesting that in the mass range analyzedand with the covering method adopted, the artificial dust powder createdan essentially single layer on progressively larger fractions of theLSC panel. By operating in waveguiding mode with powder samples oftwo different grain sizes , we observed that the relativepowercollected from the LSC edge was nearly independent of the surfacecoverage (2), this behavior was positivefor the LSCs, as it suggested that the device operation toleratedsignificant levels of dust contamination. On the other hand, the presenceof dust was critical for the solar harvesting capability of the LSC,and therefore the power output from the LSC was expected to be littleaffected by shadowing effects. In contrast, the optical interfacebetween the liquid and the PMMA waveguide resulted in severe waveguidinglosses, as illustrated in 2. Above this level,the output power saturated, probably due to the agglomeration of waterdroplets into a continuous layer whose dimensions grew by a negligibleamount with further water deposition, resulting in an essentiallyconstant average effect. Consistent with the strong perturbation ofthe waveguiding behavior of the LSC and the negligible effect of thewetting layer on the light transmittance, a very similar trend ofrelative output power with wetting level was found for the illuminationmode experiments  on the LSC panel. In this case, the overalleffect was intermediate between the dust and water situations describedabove: increasing the amount of dried residue resulted in a gradualdecrease in device transmittance, consistent with the presence oflight-scattering NaCl domains on the device surface 4a, similIn conclusion, we have studied the effectsof different types ofenvironmental agents, representing real cases in both BIPV and agrivoltaicuse of LSCs, on the performance of state-of-the-art QD-LSCs, specificallydust, water, and dried residues, separately considering their effectson solar harvesting and waveguiding behavior. We found that dust depositshave little effect on the waveguiding performance but reduce the poweroutput essentially in proportion to their mass amount . Dust deposits onthe inner surface, on the other hand, increase the power output bybackscattering transmitted light into the LSC. The most limiting factorfor light propagation was found to be the presence of wetting layersor dried residues forming optical interfaces with the LSC matrix,the latter causing a combination of the loss effects of dust and moisture.These results provide important insights into the parasitic processaffecting the behavior of LSCs and suggest that specific surface functionalizationapproaches could be implemented to favor the integration of LSCs withoutbulky encapsulation, such as the use of self-cleaning highly hydrophobiccoatings.


Despite the worldwide burden of mental illness and recent interest in global approaches to address this, progress on increasing awareness, lessening stigma, reducing the treatment gap, and improving research and training in mental health has been slow. In 2018, the North East England South Asia Mental health Alliance (NEESAMA) was developed as a collaboration between high-income  and low- to middle-income  countries to address this slow progress. This paper outlines how the joint priority areas for research, training and service delivery were identified across the life course  between partner organisations spanning Afghanistan, Bangladesh, India, Nepal, Pakistan, Sri Lanka and the UK. It describes the progress to date and proposes a way forward for similar alliances to be forged. This requires concerted efforts to tackle stigma and discrimination, improve access to mental healthcare and increase the availability of resources. Addressing these challenges requires investment in services, research and infrastructure, and a shift in cultural attitudes towards mental illness.Almost 1 billion people worldwide experience mental disorders, making global mental health an area receiving increasing attention. However, progress continues to be slow.6 Studies have shown low mental health service utilisation by ethnic minority groups, perhaps owing to a lack of culturally informed mental health assessment and intervention.7 By knowledge exchange with the global south, the global north can develop culturally informed interventions to enhance the accessibility, allocation and efficacy of mental health provision for ethnic minorities.While the global south has the challenges outlined above in mental health service delivery systems and structures, the global north has a rapidly growing multi-ethnic society, which can pose unique issues. According to the 2019 population survey in England and Wales, the Asian and British Asian communities accounted for 8% of the total population, followed by other ethnic groups.www.neesama.org) was created in response to these challenges. NEESAMA is a collaboration between partners in South Asia, including Afghanistan, Bangladesh, India, Nepal, Pakistan and Sri Lanka, and England  NHS Foundation Trust), with initial funding to support the development of the initiative provided by the British Council, CNTW NHS Foundation Trust and Newcastle University. NEESAMA aims to advance research, professional training and clinical service delivery in mental health, by establishing a partnership between policymakers, researchers and clinicians from the global north and the global south. It involves reciprocal and equitable knowledge exchange to support and facilitate improvement in mental health training and service delivery across and between all partner organisations.In 2018 the North East England South Asia Mental health Alliance  training opportunities at a discounted cost in NEESAMA countries and identification and provision of support to early career researchers (ECRs) from each country to address the research gaps.Further, clinical and research training and service development were identified as common threads across the lifespan. The lack of mental health and allied professionals in the global south has been identified as a significant barrier to addressing the mental health needs of citizens, particularly children, young people and older adults.10 The priority areas include (a) the identification of critical research questions focused on mental, neurodevelopmental and neurodegenerative disorders; (b) the identification of mechanisms for the enhancement of skill sets of clinicians working with children and adolescents, working-age adults and older adults (including the development of community-based services to cater to the needs of these age groups) and (c) ensuring the sustainability, longevity and impact of NEESAMA through the involvement of key policymakers and development of a clear and achievable action plan. www.neesama.org).The key priority areas identified by NEESAMA are aligned with the priorities in the World Health Organization's Mental Health Action Plan.11 and mental health in the context of the COVID-19 pandemic12 in international peer-reviewed journals. Additionally, rapid reviews on childhood maltreatment and mood disorders and the psychological impact of COVID-19 on child and adolescent mental health, and a scoping review on psychotropic fixed-dose combination in India, are underway. The partnership has also resulted in the adaptation of the Anxiety Scale for Children – Autism Spectrum Disorder (ASC-ASD)13 in five South-Asian languages as well as the development and evaluation of the feasibility of a novel parent-mediated group intervention to address anxiety experienced by autistic children (Helping Your Anxious Child), which is being delivered in Sri Lanka and Bangladesh. NEESAMA also awarded ECR status, following a competitive process, to eight young professionals from the partner countries to ensure the continued growth and success of this scientific enterprise.Since its inception in 2018, NEESAMA has held annual meetings (face to face and online) ensuring continued knowledge exchange between partner countries to enhance the progress of the goals and objectives of the alliance. During the last face-to-face annual NEESAMA meeting in 2019 in Bangladesh, the member countries organised a large-scale CPD panel discussion on suicide, dementia and depression across the lifespan, people in disadvantaged situations, and substance misuse at the Bangabandhu Sheikh Mujib Medical University (BSMMU) in Bangladesh. The CPD event was attended by several hundred mental health professionals in training at BSMMU. Several research projects have been conceptualised during the annual meetings and carried out in the following years. The collaboration between the partner countries has resulted in publications on geriatric mental healthFurther, NEESAMA has recently launched the NEESAMA Training and Research Academy (NEESAMA TARA), which aims to enhance the skill set of NEESAMA colleagues via a series of free, monthly online training sessions and webinars focusing on mental health that will be shared internationally through the alliance. TARA supports the ongoing objectives of NEESAMA to advance research, training and clinical service delivery within mental health internationally. Planned training events will address depression (treatment and related factors), mental health in Afghanistan, interpersonal therapy, qualitative research methods in mental health, cognitive impairment and dementia in Parkinson's disease, task shifting for maternal mental health in low-resource settings and biomarker research in mood disorders and non-invasive brain stimulation.The importance of international mental health alliances such as NEESAMA cannot be overstated. Mental disorders are a significant public health issue globally, wherein the global south contends with the problem of inadequate resources and services for mental healthcare and the global north grapples with an increasing ethnically diverse population and a lack of culturally sensitive mental healthcare provision. Thus, collaborations such as NEESAMA can foster a deeper understanding of cultural nuances affecting mental health and improve the development and delivery of culturally informed evidence-based interventions for mental illness in all the partner countries. Such alliances provide a platform for sharing knowledge, expertise and resources between partner countries to improve the quality of mental health research, education and clinical services.Alliances between the global north and the global south can have far-reaching benefits in both settings, enabling the exchange of best practices, enhancing capacity building and resource sharing, and fostering the development of sustainable and locally relevant solutions to improve mental health services. By working together, countries can develop and implement policies and interventions that are culturally appropriate to improve the lives of people affected by mental health problems.International alliances such as NEESAMA provide a valuable opportunity to bring together stakeholders across countries, regions and cultures to collaboratively address mental health challenges, leading to a more equitable and effective approach to mental healthcare globally.


The purpose of this systematic review is to provide an overview of the existing knowledge on the therapeutic potential of melatonin to counteract the undesirable effects of chemotherapy in breast cancer patients. To this aim, we summarized and critically reviewed preclinical- and clinical-related evidence according to the PRISMA guidelines. Additionally, we developed an extrapolation of melatonin doses in animal studies to the human equivalent doses (HEDs) for randomized clinical trials (RCTs) with breast cancer patients. For the revision, 341 primary records were screened, which were reduced to 8 selected RCTs that met the inclusion criteria. We assembled the evidence drawn from these studies by analyzing the remaining gaps and treatment efficacy and suggested future translational research and clinical trials. Overall, the selected RCTs allow us to conclude that melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients. Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates. Accordingly, this systematic review leads us to draw attention to the need for more RCTs to provide a comprehensive view of the promising actions of melatonin in breast cancer and, given the safety profile of this molecule, adequate translational doses should be established in further RCTs. Cancer is one of the most prevalent diseases and one of the leading causes of death worldwide , accountThe multiplicity of treatments currently available to reduce disease severity and increase total and disease-free survival, including surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapy, and immunotherapy, has been supplemented by multimodal combined therapies, which preserve therapeutic efficacy and patient life expectancy while reducing undesirable side-effects in diagnosed patients . DespiteN-acetyl-5-methoxytryptamine) is a cell protector endowed with systemic effects against many types of cancer ) AND melatonin[Title/Abstract]) AND English[Language])) NOT REVIEW[Publication Type] AND .The systematic search for the primary reports was carried out in the main repositories of biomedical information, including Medline  terms were used to reinforce the identification of all studies focused on the topic matter of the revision. Moreover, a systematic search was completed with hand searches.Reviews were excluded and studies included were restricted to those published in the English language (26 December 2022). Of the results obtained following the aforementioned search strategy, only RCTs that co-administered melatonin in combination with at least one other chemotherapeutic agent to breast cancer patients were considered. Likewise, only studies comparing melatonin administration with a control or placebo group were included. Routes other than the oral administration  of melatonin were excluded from the study.https://www.myendnoteweb.com (accessed on 26 December 2022)), and duplicate publications were automatically or manually removed. Thereafter, eligible articles were selected based on their title, abstract, or full content when required. Studies included RCTs with chemotherapy-treated cohorts and control groups. Due to the low number of RCTs available in the literature, all studies dealing with combined chemotherapy and melatonin regimens were admitted. On the other hand, any disagreement regarding eligibility and/or inclusion was resolved by consensus.Search results were exported to EndNote  for assessing the risk of bias . For eacThe domains for each study were graded as low risk, high risk, or of some concern risk of bias depending on whether available information was adequate, inadequate, or insufficient, respectively. The classification was developed independently by two authors (E.R. and A.R.), aside from the algorithm result of the RoB 2 toll. After grading, with the assistance of RoB 2 toll, the overall quality of each study was considered, and the final scores were discussed by all authors.The described protocol is fully reproducible and allows for the inclusion of emerging information through newly updated or continually updated systematic reviews, which are also known as living systematic reviews .After the algorithmic and manual screenings of the aforementioned databases, 341 records were initially identified, of which 27 duplicates were removed. Of the 314 records reviewed, 198 were considered irrelevant and 33 corresponded to animal studies. In addition, the exclusion criteria applied were non-randomized controlled studies and non-chemotherapy-treated patients. Finally, only eight primary studies of breast cancer patients treated with chemotherapy and melatonin could be considered for the analysis. A detailed flowchart of the selection process is represented in The summary of the risk of bias  was elabIn the literature, several in vivo studies included melatonin as a co-treatment for breast cancer models. These preclinical investigations pointed out that co-treatment with melatonin would positively influence several clinical outcomes in breast cancer patients. To establish a correlation between melatonin doses in animal studies and RCTs, we calculated the human equivalent doses (HEDs)  Table 3Table 3, The observed outcomes in the selected RCTs are not as positive for melatonin co-administration as reported in preclinical studies. Although, the RCTs with 20 mg/day of melatonin showed very promising results in reducing chemotherapy toxicity, displaying higher partial responses and higher 1-year survival rates. Comparing results with preclinical data, we observed more extensive and encouraging findings as HED doses increased.When effective animal doses were extrapolated to humans, the HED ranged from 1 to 486 mg per day. The eight clinical trials selected by the PRISMA guidelines tested doses from 3 to 20 mg of melatonin per day. This means that in most animal studies, equivalent doses calculated were significantly greater, even 24-fold greater than those administered to breast cancer patients in RCTs.Systematic methods based on standardized and explicit protocols make it possible to compile relevant research (primary papers or reports) related to a specific question (a topic of interest) and analyze the information according to objective quality criteria. The backbone of the systematic reviews is schematically reflected in the flow diagram in order to facilitate future reproductions and/or updates of the results and conclusions reached at any time. Thus, the present work is the first systematic review providing a comprehensive analysis of the evidence regarding the effectiveness of melatonin in counteracting chemotherapy-induced toxicity in breast cancer patients. The broad pleiotropy of this indoleamine gives it a presumed pivotal role in many signaling pathways impaired by malignant transformation and, due to its anti-estrogen activity, it is suggested as an ideal candidate for the prevention and/or regulation of the response to treatments. Thus, as far as breast cancer is concerned, diverse recent studies have pointed out that supplemental melatonin can synergistically potentiate drug cytotoxicity. Thus, in vivo and in vitro evidence in breast cancer cells support adjuvant melatonin-sensitized therapy-resistant, primary HER2-positive breast cancer cells for chemotherapy through increased oxidative stress in the endoplasmic reticulum . SimilarIn view of the functional biology of melatonin in breast cancer, the PRISMA methodology allowed the selection of RCTs that addressed this issue and evaluated the protective effects of oral melatonin in breast cancer patients treated with chemotherapy. Additionally, some promising evidence has been reported, such as the finding that topical melatonin counteracts the effects of radiotherapy in breast cancer patients . To dateAdditionally, we first calculated the translational doses of melatonin from the preclinical studies with animals to HED values and subsequently compared them to the doses used in RCTs to interrogate whether doses from experimental studies would be effective for human patients with breast cancer. Of note, the doses used in the reported RCTs have shown melatonin to be effective in reducing chemotherapy-induced toxicity at doses of 10 to 20 mg/day, as well as improving tumor regression rates at doses of 20 mg/day. RCTs with lower dosages of 3 mg/day revealed that melatonin improved sleep quality and fatigue. Mills et al.  observedRemarkably, no serious adverse effects were reported in these eight RCTs as a consequence of melatonin co-treatment. Moreover, several chemotherapy-induced toxicities, such as thrombocytopenia, myelosuppression, malaise, asthenia, stomatitis and neuropathy, leukopenia, and anemia or cardiac complications, were less common in melatonin-treated patients ,50,53,54Several limitations should be considered when reaching conclusions from the selected RCTs for this review. These limitations include the small number of RCTs performed that were available in the literature. Concerning the methodology of the RCTs, the lack of blinding the participants  increases the risk of incurring biases. However, objective assessments of patient outcomes would not likely be altered by insufficient blinding. Nonetheless, the heterogeneity of chemotherapy cycles and outcomes limited general conclusions because they made direct comparisons or meta-analyses on the efficacy of melatonin as a coadjuvant in breast cancer therapy impossible.One of the limiting factors that prevent the direct extrapolation of the results from animal studies to humans is the fact that experimental animals  tend to be nocturnal, whereas humans are diurnal. Intriguingly, circadian rhythm patterns can affect cancer development and progression . NocturnMelatonin is used as part of circadian-based regimens to maximize drug efficacy and tolerability (oncochronotherapies) by timing the delivery to match the body’s circadian rhythms. Thus, it has been suggested that administering melatonin at the appropriate phase of the circadian cycle may enhance its anti-tumor activity and reduce the side effects of chemotherapy and radiation therapy . In thisA great number of in vivo and in vitro reports on the efficacy of melatonin and its mechanisms of action against cancer models can be found in the literature ,97, inclDespite numerous animal-based studies available in the literature, only a few clinical trials confirming the benefits of melatonin co-treatment for breast cancer patients have been developed. The eight RCTs included in this review provide evidence for the safety and positive outcomes of melatonin as a therapeutic agent. However, these results are not sufficient evidence to conclude that clinical co-administration of melatonin may be effective due to the small number of trials carried out and the heterogeneity of treatment conditions and, consequently, of the outcomes reported. Furthermore, the doses to be administered in future RCTs should be reconsidered since we demonstrated that the direct extrapolation of effective doses in animal models to humans leads to doses that are likely too low to significantly influence tumor regression, metastasis, and/or angiogenesis. Therefore, more RCTs with more accurate melatonin doses are needed to confirm whether this indoleamine can generate synergies with chemotherapy that improve outcomes in breast cancer patients. In this regard, the potential benefits of melatonin co-treatment in improving the quality of life for cancer patients make it a promising avenue for future research.


Inflammasomes are cytosolic multi-component signaling platforms critical to the innate immune response to infectious diseases and the dysregulation of their activation can lead to the development of neurodegeneration and cancer.We aim through this review to ass a possible interplay between dysregulation of inflammasome activation, development of chronic inflammatory disease and enhancement of behavioral abnormalities.We comprehensively review the scientific literature using Pubmed database and other search platforms such as Google scholar to assess the role and the actors of chronic activation of inflammasome signaling complexes to establish a potential association between dysregulation of inflammasome activation, chronic inflammatory disease and enhancement of behavioral abnormalities.Our bibliographic review revealed that dysregulation of the inflammasome is associated with the onset and progression of several autoinflammatory and autoimmune diseases, including cryopyrin-associated periodic fever syndrome, familial Mediterranean fever, rheumatoid arthritis, and systemic lupus erythematosus. These multimeric complexes form in response to molecular patterns unique to pathogens and cellular damage, triggering a cascade of downstream responses, including the induction of pyroptotic cell death and release of proinflammatory cytokines. Some inflammasomes directly recognize these patterns, while others indirectly sense these patterns through changes in the homeostatic environment of the cell. Moreover, although being a normal part of the skin flora, yeasts of the genus Malassezia are associated with several inflammatory skin diseases including pityriasis versicolor (tinea versicolor), atopic eczema, psoriasis, Malassezia folliculitis and onychomycoses. In the context of tolerating fungi during colonization and eliciting, activation, of inflammasomes signaling complexes, has been identified as an integral part of antifungal host defense. While the activation of inflammasomes mainly the NLRP3 one, was shown to be pivotal for innate immunity against pathogenic fungi such as candida albicans, their role in the fungal genus Malassezia remains imprecise. Even though, many observations suggest that simultaneous activation of NLRP3, NLRC4 and AIM2 inflammasomes may play an important role.Whereas, chronic inflammasome activation such as by chronic infectious has been tied to the development of metabolic syndromes, neurodegenerative diseases, and cancer progression, a possible interplay between chronic invasion by the genus Malassezia, vigorous immune response to eliminate invading fungal pathogens, disruption of immune sensors of genotoxic stress, development of chronic inflammatory disease and behavioral abnormalities may be a new field of scientific researches.None Declared


Smoking is a major public health problem in most countries and usually occurs in marginalized groups. Analyzing the smoking behavior of migrant workers, a marginalized group in China, is of practical significance. Using panel data from the China Health and Retirement Longitudinal Study (CHARLS) database from 2013 to 2018, this study examined influence factors of smoking behavior (whether to smoke and smoking frequency) among migrant workers in China through the Heckman two-stage model. The results showed that the smoking rates of migrant workers were positively associated with social activity and a sense of loneliness, while smoking frequency was negatively associated with work stress and life satisfaction. Meanwhile, smoking behavior was associated with the demographic variables such as gender, age, and education level. Gender differences in smoking behavior were particularly notable among Chinese migrant workers. Furthermore, there was regional heterogeneity in smoking behavior among migrant workers. Smoking behavior in the eastern region was mainly influenced by psychological factors of wellbeing, such as social activity and life satisfaction, while it was affected by material conditions such as income in the central-western region. Effective strategies to control tobacco use among migrant workers are proposed in order to promote social integration between urban and rural residents, increase vocational education and training, and strengthen anti-smoking propaganda among migrant workers. As the World Health Organization 2021) pointed out, there were over one billion people smoking globally, which accounted for approximately one-seventh of the world’s population. Tobacco-related diseases result in the death of approximately eight million people each year, leading to a loss of 1.4 trillion US dollars to the global economy  pointed ,4. The CChina is a large agricultural country and the rural resident population was 509.79 million in 2021, accounting for 36.11% of the total population . Over thPrevious studies have shown that cigarette smoking and alcohol drinking are prevalent behaviors among migrant workers and that over 60% of the groups have a history of smoking or drinking, with the majority being in their prime years . It has Despite the numerous studies conducted by scholars, both domestically and internationally, on the smoking behavior of migrant workers or transnational migrants and its influencing factors, the existing literatures are often based solely on the use of certain cross-sectional data to measure the smoking behavior of migrant workers via the use of either a comprehensive index or a single dimension. There is still further space to explore by combining multiple dimensions. Therefore, this study used panel data from the China Health and Retirement Longitudinal Study (CHARLS) database over the period of 2013–2018 to analyze the smoking status, gender difference, influence degree and regional differences of migrant workers in China from the perspectives of social interaction, work stress and life stress. The main concepts and framework structures are displayed in The purpose of this paper was to examine the prevalence, gender difference and influencing factors of smoking behavior, including whether to smoke and smoking frequency. Particularly, we highlighted the effect of social interaction, work stress and life stress on the smoking behavior of migrant workers. The remaining structure of this paper was as follows: the second part introduced the data source, variable selection and model method, and generated descriptive statistics on the data and basic variables; the third part was the result analysis, including regression results, regional heterogeneity analysis and robustness test of the model; the fourth part further deepened and expanded on the research results and their significance; and the fifth part summarized the main conclusions and proposed relevant suggestions for tobacco control measures that target migrant workers.http://charls.pku.edu.cn/en (accessed on 26 June 2023).The data used in this study all come from the China Health and Retirement Longitudinal Study (CHARLS) database. The CHARLS is a set of high-quality micro-survey data comprising Chinese adults aged 45 and over and their family members for scientific research . The basIn this study, we used the CHARLS database from the 2013, 2015 and 2018 waves to create a non-equilibrium short panel dataset that included migrant workers who completed the follow-up. One of the many attractive features of this dataset, which makes it particularly suitable for our empirical analysis, is that it provides not only rich sample information such as demographic background, employment status, income, health status and other contents, but also provides specific variable information closely related to smoking behavior and social interaction. Due to the age limit of the survey samples in the CHARLS database, we focused in this paper on the subgroup of migrant workers aged 45 or above, with an associate degree or below and a rural household registration, who had worked in non-agricultural jobs for more than three months. According to the samples of migrant workers in 2013, those of 2015 and 2018 matched. After removing unmatched data and missing samples, we finally obtained 1164 data observations covering 388 survey samples suitable for use in tracking investigations over three consecutive waves.Smoking behavior is a progressively developing process and one of the addictive behaviors. According to the FCTC proposed by the WHO in 2003, smoking is defined as a behavior that includes possessing or controlling lit tobacco products, regardless of whether smoke is actually inhaled or exhaled. In this study, we measured the smoking behavior of migrant workers using two variables: one was smoking status, namely whether the interviewee smokes ; the other was smoking frequency, namely the number of cigarettes smoked per day among smokers. Therefore, the prevalence of smoking among migrant workers can be evaluated .Given that stress is a multi-dimensional and general concept, this study designed two stress dimensions, including work stress and life stress, by taking into account the main stress sources faced by migrant workers. Work stress referred to the stress caused by heavy workloads, changes in job positions and high job responsibilities. The main measurement indicators in this study included work stress, working time and income, which corresponded to direct questions in the CHARLS questionnaire such as “What is the after-tax salary including bonus in the last month?” and “How many hours did you work per day on average in the past year, excluding meal breaks but including any paid or unpaid overtime?” To account for life stress, this study considered daily work income and basic expenditures with reference to the minimum living standard, i.e., the international poverty line released by the World Bank in 2022 , measureThe key explanatory variable frequently used was social interaction, including social activity, social number and sense of loneliness. Specific information about social interaction was mainly obtained through the questions in the CHARLS questionnaire, such as “Have you done any of these activities in the last month? ”, for which there were 12 options, and “I felt lonely?” Appendix . AdditioTo better examine the significance level of the impact of explanatory variables on the dependent variables, this study controlled the impact of individual characteristic variables, such as gender, age, education level and marital status. In this study, although individuals aged 45 or above and 65 or below were strictly selected, taking into consideration the increase in the average life expectancy in rural areas and the phenomenon of incomplete retirement among rural residents, the age ceiling for migrant workers was extended to appropriately 70 years old. In the CHARLS questionnaire, education level was limited to the junior college level and below. It specifically included eight standards of educational attainment: illiterate, incomplete primary school, sishu/home school, elementary school, middle school, high school, vocational school, and two/three-year-college or associate degree. Marital status encompassed six specific categories: married with spouse present; married, but not living with spouse temporarily for reasons such as work; separated, divorced; widowed; and never married.All statistical analysis was performed using StataMP.17 software and descriptive statistics for the variables are presented in When the issue was analyzed via the work dimension, the income per month of migrant workers has exhibited a rising trend , in lineWith regard to control variables, more than 77% of migrant workers in the sample observation were male , indicatAfter conducting data preprocessing, this study performed a chi-square independence test to examine the relationship between social activity, smoking behavior and gender. The left part of Smoking behavior involved two indicators in this study, which were whether to smoke and smoking frequency. Smoking status was a binary dependent variable, indicating whether someone smoked or not, while smoking frequency referred to the consumption number of cigarettes. Obviously, non-smokers did not have a consumption number of cigarettes. Smoking behavior is clearly a two-stage decision-making process. In the first stage, it was necessary to identify whether the migrant worker had a smoking behavior, i.e., screening smoking samples. In the second stage, the smoking frequency of migrant workers who smoked was analyzed by examining the daily consumption number of cigarettes (how many cigarettes smoked per day). Therefore, this study chose to use the Heckman two-stage model to explore the influencing factors of smoking behavior among migrant workers.The Heckman two-steps method was proposed by Heckman (1979) . One of In the second step, the inverse Mills ratio (used to estimate the likelihood of selection bias variables) is included as a control variable in an ordinary least-squares regression model. It allows researchers to further analyze the effective variables that influence the smoking frequency of smokers using the sample of migrant workers who smoke.This study conducted the Heckman two-stage model to analyze its results using StataMP.17 software, and the results were presented in According to the estimation results , the firAfter introducing work stress as an independent variable, the regression results of model (3) compared to model (1) showed that in the first stage, the positive impact of work income, social activity, and life satisfaction on whether migrant workers smoke significantly increased, without considering control variables. In the second stage, the independent variables of income, social activity, and life satisfaction had significant negative impacts on smoking frequency among migrant workers at 10%, 5%, and 1% levels, respectively. With the control variables present, the regression results of model (4) showed that, in the first stage, the positive impact of social activity, sense of loneliness, and control variables of gender and age on whether migrant workers smoke were consistent with the model (2). During the second stage, the independent variables of life satisfaction and work stress, as well as the control variable of all levels of education, had significant negative impacts on smoking frequency. Specifically, the control variable education level had a negative impact at the 10% level, while the impact of the independent variable work stress was significantly less than 0 at the 1% level. This suggested that, as work stress increased, migrant workers faced more physical work and longer working times. These conditions could lead to social time tension and energy consumption, thus reduced the contact between migrant workers and smokers.In summary, the independent variables of social activity and sense of loneliness had notable positive impacts on the first stage of the Heckman two-stage model, regardless of whether control variables were implemented. During the second stage, the independent variables of life satisfaction and work stress demonstrated a significant negative impact on smoking frequency among migrant workers. However, after accounting for other control variables, gender and age had noticeable positive impacts on whether migrant workers smoked, while the independent variable of income no longer had a significant impact on the two-stage decision-making process of smoking behavior. As work stress continued to be introduced as an independent variable, the control variable of education level had a significant negative impact on the smoking frequency of migrant workers. Additionally, it also strengthened the negative impact of the independent variable of life satisfaction on their smoking frequency.In general, there were significant differences in economic development, social culture and customs among different regions, all of which could potentially have diverse effects on the two-stage process of smoking behavior among migrant workers. Considering the migration flow directions of migrant workers in China, this section examined the eastern region and central-western region as sub-samples on the basis of the models (2) and (4). The results are shown in The sub-sample regression results from model (2) were inconsistent with the impacts revealed in the entire sample analysis . NotablySimilarly, in the first stage, the sub-sample regression results from model (4), involving the independent variable of work stress, showed that, compared to the entire sample, the impacts of the independent variable of social activity and the control variables of gender and age were considerably enhanced in the eastern region, while the independent variable of life satisfaction showed a notable negative impact. In the central-western region, the impacts of the independent variables of income and sense of loneliness were significant, while the impact of social activity was not significant, and the impact effect of the control variable of education level was noteworthy. During the second stage, the independent variable of work stress had a significant negative impact on the smoking behavior of migrant workers in both the eastern and central-western regions, while life satisfaction did not show significant effects. However, the central-western region was still affected by social activity. In addition, the influence of control variables in the eastern region was consistent with the effects seen across the entire sample, but the central-western region was only significantly affected by marital status. Overall, the results were largely consistent with the sub-sample regression results of model (3), albeit without the inclusion of the independent variable of work stress . The infGiven that this study used the Heckman two-stage model to perform empirical analysis, the endogeneity issue with regards to sample selection had been eliminated. To further validate the robustness of the regression results mentioned above, this study also used Winsorization, core variable replacement and sub-sample regression methods. Among these methods, the sub-sample regression results are presented earlier in the heterogeneity analysis  and are Winsorization. This study used Winsorization to perform truncation correction on continuous variables by removing extreme values within the upper and lower 1% and 5%, respectively, in order to eliminate the biased influence of extreme values on the model’s regression results. The specific robust regression results could be found in model (5) and (6) in Core variable replacement. On the one hand, work stress and life stress were used as replacement variables for the variable of income in this paper. We chose to do this since life stress was a relative value of income and living expenses, while work stress involved working time and indirectly affected income. Model (7) in The empirical results of this study showed that social activity and sense of loneliness had significant positive impacts on whether Chinese migrant workers smoke, while work stress and life satisfaction had significant negative impacts on their smoking frequency. These results were consistent with previous studies ,26,35,36Inconsistent with previous findings in the literature ,41, we fFurthermore, the results of our analysis in this study supplemented and broadened existing research. Regarding regional heterogeneity analysis, the primary factors influencing smoking behavior among migrant workers varied across different regions. Specifically, smoking behavior in the eastern region was mainly influenced by social activity and life satisfaction, while smoking was influenced by income in the central-western region. Overall, this highlighted the impact of psychological well-being in the former, and material conditions in the latter. These findings were consistent with current conditions in which the eastern region of China leads in economic development, social openness and spiritual civilization compared to the central-western region . At the Our interpretation of the regression results is constrained by certain limitations in this study. Firstly, the measurement of stress, including both work and life aspects, mainly relies on relative indicators and lacks the self-evaluation of work and life stress from migrant workers. Meanwhile, the CHARLS database is a typical longitudinal data source, and its variables are usually measured by a single item, meaning that the reliability and validity of the scale cannot be validated. Secondly, regional heterogeneity analysis in our study needs to be improved. Although we divided the entire sample into two groups, the eastern region and central-western region, respectively, the sample size between these two groups differed significantly, with more samples taken from the eastern region. This may impact the analysis results presented in this study. Thirdly, our original empirical logic aims to test the impact of different stress indicators on smoking behavior (whether to smoke and smoking frequency) by sequentially adding the variables of work stress and life stress as determined based on the benchmark model. However, because the measurement of life stress in this paper is based on the relative value of income and expenses, there is collinearity between income and life stress. As such, taking the life stress variable as a part of robustness test of the model also better satisfies our initial research hypothesis. Additionally, smoking history (the number of years of smoking) may be a potential factor affecting the smoking frequency of migrant workers.Population aging currently poses a great challenge to the family and to the social public service system. The Chinese migrant worker population is also experiencing aging, and there is a phenomenon of intergenerational shift occurring within the group whereby the new generation of migrant workers, especially those born in the 1990s and 2000s, are gradually becoming the main force in urban development. Due to the different influences of growth environment, educational and cultural background, the new generation of migrant workers differs significantly from their older counterparts in terms of value pursuit, behavior, consumption habits and so on. Furthermore, the topic of retirement and re-employment for migrant workers who have exceeded the typical retirement age has also been widely discussed by society. These are essential aspects of social life that urgently require more attention in future research.As the mortality attributable to smoking continued to increase, tobacco smoking will remain a major public health problem in most Asian countries in the coming decades . MigrantFirstly, the empirical analysis in this study indicated that social interaction and a sense of loneliness were found to have a significant positive impact on whether Chinese migrant workers smoke, while work stress and life satisfaction had a significant negative impact on the smoking frequency of those. Therefore, in the context of urban–rural integration and development, it is vital to strengthen social integration in order to improve life satisfaction and reduce sense of loneliness. Such an approach is crucial for controlling smoking behavior among migrant workers and, if implemented, would have a positive impact.Secondly, smoking behavior among migrant workers was also influenced by factors such as gender, age, and education level. The gender difference in smoking behavior among Chinese migrant workers was particularly notable. We also found that the smoking rate among migrant workers increased with age, but that those with a higher level of education were more likely to keep their smoking frequency to a lower level. Therefore, it is essential to strengthen anti-smoking propaganda and promote the development of vocational education and training in rural areas. Such initiatives would raise awareness about the harmful effects of smoking among rural minors and enhance the overall education level and quality of migrant workers.Finally, this study also examined the regional heterogeneity of smoking behavior among Chinese migrant workers. The results showed that in the eastern region of China, smoking behavior was primarily influenced by psychological well-being factors such as social activity and life satisfaction. Conversely, smoking behavior was more significantly influenced by material conditions such as income in the central-western region. Of course, more scientific research is necessary to further validate these findings.


The primary focus of research in food production revolves around ensuring food quality and safety. Consequently, there is a significant interest in establishing dependable approaches to detect, identify, measure, describe, and monitor any quality and safety concerns that may arise in food production. To enhance the efficiency of production processes and maintain high-quality standards, the food industry also requires tools that can minimize waste, promptly identify potential process issues, and reduce the need for extensive laboratory analysis. These tools aim to streamline operations and reduce the workforce dedicated to such tasks.This Special Issue brings together new strategies and applications that address these needs in the food industry. The development of new analytical sensors or new analytical methods that can be used in the field, if possible, using as few solvents as possible  and analysing the sample as it is, without or with minimal pre-treatment, was the primary focus of this Special Issue. The optimisation of reagentless methods with no or minimal pre-treatment, also leads to the advantage that that method, suitably adapted, may also be successfully used for the direct control in the production process itself.The abundance of literature on the subject reinforces the fact that spectroscopic techniques are highly suitable for such applications. The availability of affordable and portable spectroscopic instruments has the potential to bring significant advantages in food quality control. NIR (near infrared) and Raman techniques are the most widely used, with a large prevalence of applications in the NIR range. Virtually all the applications involving spectroscopic instrumentation require multivariate data processing to extract the relevant information from the spectra, very often starting from principal component analysis (PCA) as a method of data visualisation to multivariate regression techniques  or classification techniques, depending on the problem to be solved. The methods used are mainly linear, except in some specific cases where non-linear methods perform better, as is evident from the articles in this collection.Jean Frederic Isingizwe Nturambirwe and co-authors  conducteCompact solids are often analysed with miniaturized instruments. However, when it comes to analysing liquids, researchers often need to develop strategies specifically tailored to this objective. As an example, Giussani and co-workers  demonstrA very interesting application was presented also by Zhiyang (Stan) Tu  and co-wAs the evidence supporting the effectiveness of miniaturized NIR instruments in food-related applications continues to accumulate, there is a growing number of end-users adopting these instruments, partly due to their affordability. While considerable attention is given to the analytical protocol, including sampling, data collection, and data processing, the significance of investigating errors in raw data is often overlooked. Giulia Gorla and co-authors  proposedUndoubtedly, one of the most extensively studied samples globally is milk, encompassing both commercial food products and breast milk. In this collection of articles, as many as three out of fourteen (more than 20%) are dedicated to milk analysis. Christopher Karim Akhgar and colleagues  proposedFinally, Yanan Xia and co-workers studied the variation and correlation of different flavour parameters and bacterial diversity of low-salt hotpot sauce during storage . Multiva