The SARS-CoV-2 (COVID-19) pandemic has contributed to increasing levels of anxiety, depression and other symptoms of stress around the globe. Reasons for this increase are understandable in the context of individual level factors such as self-isolation, lockdown, grief, survivor guilt, and other factors but also broader social and economic factors such as unemployment, insecure employment and resulting poverty, especially as the impacts of 2008 recession are still being felt in many countries further accompanied by social isolation. For those who are actively employed a fear of job and income loss and those who have actually become ill and recovered or those who have lost family and friends to illness, it is not surprising that they are stressed and feeling the psychological impact. Furthermore, multiple uncertainties contribute to this sense of anxiety. These fears and losses are major immediate stresses and undoubtedly can have long-term implications on mental health. Economic uncertainty combined with a sense of feeling trapped and resulting lack of control can contribute to helplessness and hopelessness where people may see suicide as a way out. Taking a macro view, we present a statistical model of the impact of unemployment, and national income declines, on suicide, separately for males and females over the life cycle in developed countries. This impact may reflect a potent combination of social changes and economic factors resulting in anomie. The governments and policymakers have a moral and ethical obligation to ensure the physical health and well-being of their populations. While setting in place preventive measures to avoid infections and then subsequent mortality, the focus on economic and social recovery is crucial. A global pandemic requires a global response with a clear inter-linked strategy for health as well as economic solutions. The models we have constructed represent predictions of suicide rates among the 38 highly industrialized OECD countries over a period of 18 years (2000–2017). Unemployment has a major effect on increasing suicide, especially in middle-aged groups. However, the impact of economic decline through losses of national income (GDP per capita) are substantially greater than those of unemployment and influence suicide throughout the life course, especially at the oldest ages. The current epidemic of SARS-CoV-2 COVID-19) has altered the way populations deal with stressors and resulting worries. The pandemic has affected directly or indirectly every individual on the planet but with varying individual and country responses. The impact of the pandemic on health is crucial but it also affects economic, educational and political aspects of life globally. Not surprisingly, the pandemic has led to a massive number of publications and research observations from cross-sectional to observational data on people in quarantine, self-isolation, shielding and others. A considerable and increasing number of professional society warnings and academic papers strongly suggest that the COVID-19 pandemic has resulted in anxiety- and depression-related illness, and potentially, suicide 9 has alt. These sIn this paper, our focus is mainly on the mental health effects of this corollary to COVID-19 based strictly on damage to the economy. However, it is still too early to ascertain either what the intensity and duration of COVID-19 will ultimately be, or how it will affect national economies . In thisThere has, rightly, been considerable epidemiological and media attention to the highly differential effects of COVID-19 as well as its economic implications on ethnic minorities and low socioeconomic populations in the industrialized world , 15. It The principal aim of this paper is to identify the secondary effects of economic disruption in relationship to COVID-19 as these effects accelerate anxiety, depression and, especially, suicide. A statistical model of the impact of unemployment and national income declines on suicide, separately for males and females over the life cycle in developed countries during 2000–2017 will be central to the pinpointing of secondary effects of abrupt national recession. Suicide, in this case, is taken as a classic empirical indicator of anxiety, depression and anomie. This model thus provides the basis for estimating the potential simultaneous and lagged impact of unemployment and economic decline on suicide that accompanies the economic recession (and continues to be) intensified by COVID-19. Such a model allows us to anticipate the “purely” economic effects of COVID-19 on suicide, without considering the direct mental or physical health consequences of the COVID-19 infection. This permits consideration of the separate effects of economic recession that are amenable to policy mitigation through e.g., income support of the unemployed , small and large businesses that are damaged or terminated, and nationally financed investment in healthcare and educational personnel and social welfare. This analysis provides a structural basis for economic and health policy makers to take into account the mental health consequences of their prospective decisions. At the same time, the statistical models provide a basis for understanding the economic and political foundations of national-level suicide rates and their relations to official mental health-based diagnoses of elevated mortality, anxiety and depression. An additional aim is to provide an overview of the epidemiological history of national economic and unemployment risk factors to suicide. Finally, we offer suggestions as to psychiatrically-oriented policies that could be used to mitigate the current mental health effects related to the economic accompaniments of COVID-19 in The Way Forward.The general theme garnered among reporters and some writing in professional journals is that there are two clear implications for harm to mental health resulting specifically from the COVID-19 epidemic. The first is that people are simply “fearful” of going to work and appearing in public gatherings for fear of infection and mortality—especially among those with chronic cardiovascular, diabetic or asthmatic conditions as well as persons over 65. Additionally, there is the active and palpable fear of job and income loss, not only by those who are concerned about returning to normal social life, but those who have actually become ill or lost family and friends to illness and mortality in the COVID-19 pandemic as well as those who had insecure jobs in the first place. There is beginning to be some subjective reportorial literature pertaining to grief, without reference to the very extensive academic literature on stress, but with tacit or implicit knowledge that such fears and losses pertaining to health are major immediate stresses and can have long-term implications on mental health, analogous to those of what is now understood to be a classic PTSD series of events. In days of lockdown, with the loss of family members and inability to attend their funerals or even say goodbye itself can be seen as traumatic events.But how can we reasonably predict—even in scenario terms—what the effects of COVID-19, and its corollary mental health disturbances would really look like? It is necessary to get answers to this in order to plan for public health, medical, economic, and specifically mental health policies.However, in none of these suggestive articles are there any statistical analyses , 17, 18.fear of the COVID-19 infection itself and related mortality, as well as of potential losses of employment and income associated with that infection. Entirely missing thus far, however, has been data that would deal with a recent period of time where recessional economic losses have quantitatively influenced mental health without the influence of a major infectious pandemic. We would thus need to develop an empirical basis for understanding how, in the COVID-19 pandemic era, a significant proportion of measures of disturbed mental health would be influenced by deterioration of the economy—apart from what the COVID-19 implications of fear of infection and mortality would separately have on mental health.The principal intellectual challenge for this paper is to produce evidence that will allow us to develop scenarios as to how the most current recession, based on shutdown of national economies in relation to COVID-19, will ultimately influence population mental health. Once again, it has been seen as “obvious” in journalistic accounts that the main mental health effect would arise out of This is not such an unusual problem, but rather one that has been more recently discovered as a potential epidemiological quagmire. We find this problem of separation of effects in virtually all major disaster research, where the primary research impulse is to identify the earliest short term influence of the disaster  on those who immediately experience the disasters in terms of their on-the-spot threat to their lives and health. However, the losses of homes, occupations, family relations, and the elements of civilization surrounding the disaster have often been assessed in terms of their implication for mental health but not with COVID−19. This is the case, although it has been clear from the beginnings of research on life events, that these secondary, or corollary, phenomena influencing the direct economic and social relations consequences of the disaster, could have at least equal impact on the longer-term health situations  or a result of economic pressures. Add to this the common assumption among epidemiologists that all deaths are the subject of multicausal factors, and comorbidities, and under the best of circumstances determination of an overall causal risk of mortality due to suicide is fraught with intellectual and societal problems.Further, exacerbating this issue of definition lies in trying to determine time sequences. Thus, the heightened risk of suicide due to alcohol abuse may result in mortality that is not easily attributable to suicide, but the reaction of a loved one to such mortality could eventuate in suicide. Such reactions are not uncommon in the case of widow or widower suicides upon learning of the deaths of a spouse, for example –22. And The ultimate definitional question then is to what degree do deaths attributable to factors such as accidental poisoning, traffic accidents, or drug abuse represent suicides and need to be added to the category of suicides, perhaps in a broader concept such as “deaths of despair.” Another complicating factors is what Durkheim called anomie (in this case caused by the pandemic) and deserves further detailed study.An additional estimation problem arises when, as in the current analysis, we deliberately include different countries, so as to try to bring about a general understanding of the factors influencing suicide as a human problem, rather than one confined to suicide in a given country. These issues may be distinct from those of definition or other cultural or legal determinants which make suicide more or less likely in a specific society. The key problems here are cultural determinants of suicide including such elements as honor, bravery, social integration, individualism, meritocracy, and—perhaps especially—religion and its taboos with respect to taking one's own life. A related issue of cultural determination arises in discussion of gender differences in suicide. Here, considerations are generally given to masculinity and/or its assumed attributes of risk taking, bravery or dominance.Combined with economic factors and a sense of feeling entrapped and consequently a lack of control can contribute to helplessness and hopelessness seeing suicide as a way out thereby combining the impact of social changes due to anomie and economic changes as a result of the pandemic.As yet, no statistical evidence exists for the very recent effect in the COVID-19 era of the radical increase in unemployment —without the direct effects of COVID-19. There have been extensive qualitative discussions of the impact of unemployment on mental health outcomes in journalistic reports and academic papers very recently. These accounts have made reference to anecdotal data through interviews and literature reviews, and typically have made reference to how this might be playing out in real time, considering the great magnitude of such potential effects given a potential 15–20% unemployment rate. Several of these references made inferences from the most recent dramatic increase in unemployment occurring in the Great Recession of 2007–2009, when no major infectious disease epidemic occurred. Rather, the period just prior during, and following, the Great Recession was one which coincided with several mental disorder-related trends in industrialized societies. These include epidemic-like movements in alcohol consumption and abuse, drug abuse, drug poisonings, unintentional accidents, divorce rates, and other indications of family instability such as inter-personal gender based violence, child abuse etc. On the other hand it is recognized that high body mass index often attributed to behavioral factors can make people more vulnerable to COVID-19 related deaths , 25. BMIThus, multifactorial origins of several damaging mental health trends, from the potential mental health effects of COVID-19 itself start to emerge. However, in the current COVID-19 era these journalistic reports and scientific papers have almost uniformly failed to recognize the major distinction between the mental health sequelae of COVID-19 as an infectious disease process from the accompanying massive recessional effects brought about by efforts to contain the pandemic. Yet, familiarity with the mental health effects of national economic disturbances should very quickly have focused researchers' attention on the potential and great magnitude of anxiety and depression implications of massive national unemployment rates and losses of income and wealth arising out of losses in GDP per capita, wages, and social welfare outlays. It is entirely possible that countries often have clear economic plans and strategy but do not have a mental health plan or policy as Bhugra et al. in a survey of Commonwealth countries reported that less than half of the members had a mental health policy .How can we develop an estimate of the potential separate and indirect effects of COVID-19 recessional losses on mental health—being a corollary effect of COVID-19—from the direct effects of the pandemic itself on compromised mental health? The easiest way to accomplish this is to examine the most recent period of large-scale employment and income losses on mental health, in the absence of the COVID-19 pandemic. That reference would be to the Great Recession and its aftermath, with large-scale economic damage, but over (what is now in the COVID-19 era) a shorter period.In having a numerical estimate of the effects of the Great Recession on mental health outcomes, it would be possible to make a comparison to that of national economic disturbance during varying periods  of the COVID-19 pandemic. The challenge then would be to estimate, for example, the numerical implications of an increase in unemployment during the Great Recession with a similar actual numerical increase in unemployment during the COVID-19 era.In developing such estimates of the actual vs. the potential impact of national recession on mental health outcomes, it is, in our view, of great importance to additionally separate the effects of short- and long-term losses of employment from the effects of income loss. The reason is that even in very major recessions only a minority of the population suffers employment loss, while actually a substantial majority of the population suffers losses of income and wealth. To put the income issue in broader perspective, it should simply be pointed out that virtually any goal of individual persons in their ordinary life adaptation and behavior, from food security, poverty minimization, and obtaining the worthwhile things in life in a market economy, requires finances. At the national level, income per capita also involves government revenues which are essential to the provision of health care, education, scientific and technological investments—often in the biomedical sphere. And for the younger population, the income base is essential for career development, social mobility and family formation that are fundamental goals. Interestingly, there have been very few studies that have separately examined the effects of income loss in the short term, and especially in the long term given government policies of austerity, on mental health implications apart from employment losses. An intermediate literature, lying between company losses and employment losses has in the last several years been concerned with firm downsizing—especially in the wake of the Great Recession . This maThe absence of attention to GDP declines in previous literature on the effects of recession on mental health is particularly problematic, since welfare payments, including unemployment payments and assistance to firms in maintenance of jobs, as well as health care access and expenditures, have suffered considerably with the decline in government revenues which have been the basis of austerity budgets. These have been largely evident in Europe but have also been documented in North America , 31.Added to the most visible outcomes of government austerity on poverty minimization are declines in government investment in education. This has not only had very serious effects on the ability of younger workers to develop careers in times of recession, but have led to longer-term effects on life time earnings and loss of productivity gains. The latter point of productivity growth diminution is estimated to have important implications for at least the next generation of workers and governments , 33.Further compounding previous analyses of mental health effects due to recession has been the lack of use of multivariable models predicting, e.g., suicide, but taking into account other major sources of risks than the immediacy of recession, such as alcohol and drug abuse or accidental mortality. And, as indicated earlier, the lack of control for such potential risks often hide significantly the inherent suicidal intent , of suicidal behavior represented by such risks. Thus, the absence of control for such factors, at the very least, increases the risk of misestimation of the actual level of suicide that is contingent upon economic damage.A perennial problem in the analysis of suicide, since at least the time of Durkheim, has been the population samples on the basis of which suicide is estimated or predicted . On the Nevertheless, the choice of overall region to be the subject of statistical analysis remains fundamentally important. This is particularly true in the case of psychiatric outcomes, where, among the world's societies, there are large distinctions as to the psychiatric reliability of a suicidal diagnosis. In this paper, we therefore focus on uniform data available from the OECD, which is largely based on data from the most highly industrialized societies. The presumption is that data from these societies on suicide are likely to respect the psychiatric and scientific conventions of mental health diagnoses, and less likely to be heavily influenced by religious or other societal stigmas that would serve to contaminate criteria for coroners or medical examiners  .In modeling the prediction of suicide in industrialized societies, it is clearly important to take into account the variety of beneficial factors that might influence societal anxiety and depression. Important in this regard are professional social welfare efforts usually through government expenditure, to manage societal mental health problems. This is especially true since the relation between lower socioeconomic status and poor mental health is so widely acknowledged it is of special importance to concentrate on issues of poverty, homelessness, unemployment or insecure employment and long-term psychiatric disability in minimizing suicide. Thus, societies are faced with the usual issues of opportunity cost as they face political decisions involving physical and mental health. To what degree does the society concentrate on basic support of material living conditions and education as distinguished from more highly medicalized attempts to improve overall health or mental health levels. This involves intense political discussions which are important here but are not the direct subject of this paper. Nevertheless, in the statistical modeling process, one needs to bear in mind not only the level of society's overall income and wealth, but rather the specific monies allocated to promote differential societal goals that also promote health. This is clearly a limiting factor in the use of the GDP per capita as a primary source of influence on mental health; yet, with a reduced GDP per capita there is less governments can achieve, regardless of their competing policies. It is clear, then, that the sheer magnitude of GDP per capita is a prime limiting factor in how much governments can accomplish in order to improve mental health.It is worth looking at the impact of COVID-19 on mental health in stages. For example, first stage of quarantine, self-isolation may bring with it certain stressors especially if individuals are living by themselves or nuclear family settings in many high income countries. Second stage will be of infection and isolation either at home or in hospital. Bereavement as a result of death of a loved one and inability to attend funerals in lockdown situations will affect coping with grief and may well-lead to abnormal grief reactions. In many countries an inability to perform rituals after a death can further add to distress and resulting depressive feelings. Some individuals may go on to experience survivor guilt. Each of these observable stages will affect mental health and well-being of individuals. In low income countries which may be socio-centric, additional pressures may play a role. Thus, the fear of catching the infection can lead to avoidance anxiety, the sense of being entrapped can lead to depression and grief reaction due to loss and bereavement followed by managing survivor guilt and each of these conditions can contribute to increased likelihood of self-harm or suicide. In all the preparations for dealing with the pandemic, the emphasis initially was on prevention and then treatment, the focus on mental health emerged later. In dealing with mental ill-health the focus must be on individual, family, community, and then national and global responses.It is common that for some observational studies, observations are available over a sequence of points in time, e.g., countries and years as in our case. Taking into account only one dimension, i.e., space or time, would restrict us to perform classical cross-sectional or time series regression analysis. Using more advanced techniques , 38, i.eThe PCSTS method combines two approaches. The more familiar is cross-sectional analysis, where, in this case, countries of the OECD are the units of analysis . We examine multiple cross-sectional analyses corresponding to the 18-year period-−2000–2017 for which all of the data representing the individual variables are available for the OECD countries. All variables used in these PCSTS analyses are based on aggregated data—i.e., population rates rather than individual-level data 1. In addPCSTS models can be regarded as extensions of a common linear regression model where for the pooled observations the error term is split up in a unit specific term and a stochastic remainder disturbance. Different assumptions about the stochastic properties of the unit specific term raise two main PCSTS models: the fixed effects and the random effects estimator. The fixed effects model assumes that the unit specific term is non-stochastic and constant over time. The random effects model treats the unit specific term as a stochastic entity. Methodological details for both models and the estimation techniques are provided in Baltagi and Wooldridge. Disadvantages of the fixed effects estimator are that it cannot deal with variables that do not change over time and that it provides imprecise estimates when variables change only slowly over time . As our PCSTS is a well-established procedure in economics over the last 30 years and has recently been introduced in health service research and epidemiology , 44. TheThree types of variables included in this model are dependent, independent, controls.Age-adjusted suicide in international WHO database, according to coroner's and/or medical examiner's, ICD code separately by sex and age—for each OECD industrialized country.Macroeconomic and unemployment variables. These are the basis of our hypothesis—as related to recession of 2008-10, depending on country.Divorce, etc.; unintended injuries (now the third highest cause of death in the United States 2020); accidents ; self-poisonings; drug overdoses; fire/burns; drownings.These above control variables could actually represent suicides but for factors relating to stigma, or classification “error” given the specifications of the ICD code, these “causes” of death may in many instances be actual proximal mechanisms of suicidal death, where the mental “intent,” e.g., a state of depression, might be the true psychological state which underlay  these mechanisms of death —and may in fact represent suicidal behavior.From a methodological point of view we want to hold constant other risks of suicide that could also be correlated with both economic changes and officially identified suicides. Without these controls, the effects of economic change could either be underestimated or overestimated.The statistical models demonstrating the sheer implications of unemployment increases and national income (GDP per capita losses) over 2000–2017 provide the basis for understanding, and ultimately estimating, the potential future mental health and suicidal impact of the recessional phenomena during the ongoing, and rapidly continuing—in terms of its consequent production of economic recession. But at this point we do not know how intense or lengthy the COVID-19 recession will be among industrial democracies of the OECD. Equally important, we have no foreknowledge of what the individual governments may invest in unemployment, business, welfare, health care, and educational relief and stimulus to maintain economic stability and mitigate poverty as COVID-19 and its sequelae proceed. It is clear that different governments are responding in different ways. Further, the epidemiological literature indicates that the economic impact of employment and income loss and poverty may lag over a range of at least 5–10 years, if not a generation. Therefore, the coefficients showing twenty-first century relations between income and employment loss and mental health, must, in practical policy discussions, be stated in terms of scenarios that refer to potential policy decisions on the part of governments.The models we have constructed represent predictions of suicide rates among the 38 highly industrialized OECD countries over a period of 18 years 2000–2017) see , 2. Ther000–2017 The third variable common to all models (irrespective of gender and age groups) is the mortality rate for substance use disorders . This ICD categorization of mortality typically represents addictive behavior or abuse of especially alcohol and illicit drugs being used for psychopharmacological reasons in mood alteration, generally not under the regulation and prescription of medical personnel. The literature is unable to fully discriminate between the effects of substance abuse that is the product of suicidal intent, from the effects of substance abuse that causally results in suicide . We include the substance abuse disorder/death rate as a means of controlling for the fact that the nationally designated suicide rate may insufficiently refer to the substance abuse death rate that involves suicidal intent or consequences.Additional variables predicting suicide among the industrialized countries are differentiated between males and females see . EspeciaThe number of potential suicide-related categories that significantly predict suicide are somewhat longer in the case of male populations as compared to females. In the case of males, the death rate category of “road traffic injuries” is significantly correlated with male suicide, as are, in addition, death rates associated with “fire, heat, and hot substances.” The literature, here again, is not very clear as to why these categories of death should be more closely associated with male suicide. However, there are studies of suicide patterns that generally indicate that males are considerably more likely to use violent means in suicidal acts, whereas female suicides are more typically associated with relatively passive methods, including substance abuse and drug overdose , 49.Male and female suicides differ considerably in their pattern of relationship to the principal economic phenomena GDP per capita and unemployment see , 4. MaleThe second period in which male suicides are highly sensitive to economic changes is after the age of 60. That sensitivity is moderately strong between 60 and 74, but rises to a peak in the ages over 75 (75–79 and over 80). Once again, this means that the period of life for males during which declines in material well-being are most likely to be associated with increased suicide are over the age of 60, and especially over 75. The age of retirement varies across countries.This is in contrast with the age specific pattern of suicide for women. In the case of females, we find, remarkably, what is virtually a linear, dose-response relationship between age and suicide. The older the age of the female population, the more likely is the occurrence of suicide in relation to declines in GDP per capita. Somewhat similar between the sexes is the unusually strong increases in suicide in the later stages of the life cycle, 75–79 and over 80 years of age. Thus, especially for women, losses of income appear increasingly important with increases in aging. And the most powerful effect of income loss in relation to female suicide is in the very late ages of life.In contrast to the relation of suicide to GDP change, for males the relationship between unemployment and suicide is highest in early and late middle age (40–64) and disappears entirely after the age of 70 see . This prIn principle, as shown in The period over 65 encompasses the ages presumably least expected to be influenced by unemployment, since unemployment is lowest at this period. At the same time, the ages over 70 are those with the highest rates of poverty in industrialized countries . And we If we now examine the relations of potential mechanisms of suicide to nationally identified suicide rates, we find similar patterns. For male substance abuse and road injury (death rates), the relation of mortality to identified suicide (death rates) come to a broad peak level at 35–54 see also . Fire, hFor women, a middle-age high level range in substance abuse mortality, correlated with female suicides, occurs at 35–39 through 60–64. But additionally high levels of substance abuse mortality related to suicide occur at the younger ages of under 19 through 30, and at the very high age range of 65–69 through 75–79. Perhaps most remarkable are the very strong correlations between female mortality identified with adverse effects of medical treatment and official female suicide rates. Unusually strong relations are found under age 30, with relatively strong relationships between the “standard” 30–54 (middle-aged) suicide rates, but no significant relations after age 54. There is a considerable likelihood that these strong relationships to suicide mortality are consequences of adverse relations to pharmaceuticals of which over 200 have been identified .There is, certainly, an extensive and lengthy set of literature in psychiatry, psychology and the newer field of psychoneuroimmunology on stress as a source of mental health disturbances of many different varieties and, especially, of anxiety, depression, and suicide –54. ThisThe scientific literature is now fairly extensive on the distinction between short and long-term effects of stress, especially as it would pertain to anxiety, depression and psychophysiologic changes. In particular, very short term stresses have been thought to actually be a source of beneficial stress—i.e., “eustress” as originally formulated by Selye . In the From the earliest days of psychiatric epidemiology –60, the Since the period of the Great Depression, Marie Jahoda, Peter Warr, and other sociologists , 64 haveIn the history of Western epidemiology, socioeconomic status is perhaps the single most consistent explanatory factor in terms of understanding the distribution of mental health problems. Social determinants have always played a major role in the genesis of physical ill-health but increasingly this is being focused on mental illnesses . One of Over the years of development of psychiatric epidemiology, income, occupational skill level and educational level have been successfully used to understand the distribution of a wide variety of mental disorders, from those which have a more definitive genetic and physiological basis, such as schizophrenia, bipolar depression and dementia to those with a broader emotional spectrum, including anxiety, depression, and PTSD. The usual inference has been toward a new interpretation involving traumatic life events, including especially health concerns and financial disturbances as well as harm to social relations, especially those involving family and close friends. These findings for psychiatric illnesses had begun to be developed in the 1930s, coinciding with the Great Depression, which is not unlike the greater concern with physiologic illnesses ranging from infection to cardiovascular disease, becoming especially prominent in the 1970s . There wThe general understanding, even thought to be commonsense in the present era, is that a lower level of human resources, including nutrition, an egalitarian and stable public health structure, higher levels of education, render the population more highly adaptable to environmental threats. But the place of income has been more widely recognized in the later twentieth and twenty-first centuries. Within predominantly capitalist cultures, money, and income is seen correctly as the source of ability to purchase virtually every sort of physical commodity and knowledge-based output, health care, intellectual advice and political engagement. Thus, where significant environmental stresses, including those of unemployment and a damaged economy were rampant, clearly the importance of income as a means of escaping from the ravages of deprivation were fairly obvious. Much of the epidemiology—especially in the British case—of social class and illness has been responsible for the more robust development of the European welfare states and the force of the intellectual expression of labor unions.Similar themes to this emerged as well in the psychiatric epidemiology of the 1950s. However, it was not until a decade or two later that psychiatric epidemiology began to focus on the macro-, or national-level significance of economic changes, especially economic development and unemployment. Moving from the individual level analyses to the macro understanding of economic changes on mental health, the beginnings of econometric analyses using techniques originally developed within the field of economics began to be used . The macBeginning in the 1980s, much less visible but significant long-term economic decline has occurred as a result of the shifting of manufacturing away from the industrialized countries and toward Asia—especially China. This is a phenomenon described very thoroughly by Autor in “The China shock” . The resSince the 1950s, one of the more sustained approaches in psychiatric epidemiology has been in the construction of scales identifying distinctive key events in the life cycle that tend to represent major changes , 78. TheAt the macro level, a substantial number of studies have continued to demonstrate the damaging impact of economic disturbances, especially recessions, involving high levels of unemployment in the United States, Europe and other parts of the industrialized world , 82–84.The question now arises as to whether relatively recent disturbances to the national economy have shown the effects of unemployment and income loss on stress-related chronic disease and mental health disturbances. Findings have demonstrated the effects of losses of wealth on mortality  and the The review by Brenner referred to earlier , also inSince our primary goal in this paper has been to ascertain the importance of changes in the economy, particularly recessions, on suicide, two outstanding observations must be noted. First, the prior literature provides robust indications that increased unemployment is a prime national predictor of suicide rates, and this is reproduced herein for industrialized countries in the Great Recession. But it is clear, that unemployment is not the most important economic predictor of national suicide rates, even though, both journalistically and in academic papers, it is the most frequently researched macroeconomic topic in relation to mental health, going back to original observations in the 1970s. This is true even though in analyses in this article, the oldest populations over 70—in the case of females and over 75 for males—do not show a relationship between national employment and suicide rates. The effects of economic loss during recessions must be seen, primarily, in terms of income loss to families over the short- and long term. Of course, such losses coincide, temporally, with recessions, during which unemployment is also high. But it is clear from these analyses that income losses, even among populations that do not lose employment are the more salient predictors of suicide rates for all age groups. In fact, the most powerful effects of income loss on suicide for both sexes are observed over the age of 70 and are outstanding over the age over 75. Therefore, it is necessary to consider the recessional effects on suicide to include a combination of GDP decline and unemployment increases.Secondly, it appears clear from these analyses that national levels of diagnostically identified suicide, in national data, probably represent a considerable underestimate of the actual suicide rate. This can be inferred from multiple literatures dealing with the effects of alcohol addiction and abuse, drug addiction and abuse, as well as poisoning-related mortality, accident-related mortality, as well as fire, heat and hot substances-related mortality see . The sepThe major question now is how the experience of the Great Recession for suicide can be forecast (be repeated) as a result of COVID-19 pandemic. The first effect that other journalistic accounts and non-statistical academic papers have strongly suggested is that the immediate effects of losses  have also materialized in the current COVID-19 limited period.However, the major effect on mental health and suicide of COVID-19 may well be a fundamentally and indirect corollary—namely, the consequent effect of economic losses due to shutdowns worldwide. Whether suicide and related mental health effects will emanate from the current COVID-19 related recession depends greatly on the length of that recession, as well as efforts to ameliorate the economic situation of people and businesses by governments. Most important will be the duration and intensity of the COVID-19 recession, but this will of course depend on the duration and intensity of COVID-19 itself as its potential secondary and subsequent waves induce an international transmission from countries in the developing world influencing, in a circulatory manner, subsequent effects on industrialized countries.The joint mortality outcomes of the COVID-19 pandemic and its corollary impact on the economic recession-induced mental health impact will depend on specific policies undertaken by individual country governments. The United States, for example, has experienced one of the most severe direct COVID-19-related mortality rates, as well as extremely large increases in unemployment rates, will likely suffer long-term economic declines (via weak economic recovery) and substantial permanent losses of jobs, life time income and wealth –97. ThisHowever, current economic policy considerations, taking COVID-19 health outcomes into consideration, still does not consider the indirect corollary implications of the COVID-19 recession in terms of major mental health outcomes and chronic disease mortality. Bearing such corollary health outcomes in mind, policy makers would be wise to include the total health gains to an expansive economic policy along the lines put forward by the International Monetary Fund (IMF), the World Bank and OECD –100.Nevertheless, even under relatively generous economic support of individuals and businesses, it is quite likely that there will be permanent job losses, especially in the industrialized countries, as a result of economic restructuring under conditions of reduced demand. We have begun to see this occur in many of the service industries, such as restaurants and bars, tourism, travel, transportation, entertainment and shopping, and even healthcare , 102. UnClearly, the most urgent policy effect must be to contain, and perhaps, eliminate COVID-19, but secondarily, and in order to facilitate public health measures, government financial sources of relief need simultaneously to be implemented.The present analysis is an estimation of the potential secondary effects of the economic recession due to the pandemic on mental health. The study is confined to the entire industrialized country populations of the OECD. Therefore, some of the special risks to suicide which are specific to each country and their sub-regions  could not be extracted and tested as control variables at this point. Similarly, since this is an epidemiological study based on aggregated, rather than individual, data, one cannot separately identify genetic differences or specific psychiatric syndromes that could represent individual proneness to suicide, especially in interaction with major economic variables such as national income (GDP per capita) or the unemployment rate.From this point of view, it is only attributes of national populations that could be entered into the predictive models—more commonly known in the economic, epidemiological, and social science literatures as macro-level analyses. This approach is very much within the theme of the classical Durkheimian view that suicide rates are, to a large extent, attributes of societal, rather than individual, characteristics. Finally, this statistical correlative analysis only permits us to make inferences as to risk factors at the national level, that relate to the magnitude and fluctuations of population suicide rates, rather than enabling inferences as to aspects of causal relations attributed to characteristics of individuals.Perhaps most important, the statistical analysis has shown that several causes of death are highly predictive of officially designated suicide deaths see . These iThe governments and policymakers have a moral and ethical obligation to ensure the physical health and well-being of their populations. While setting in place preventive measures to avoid infections and then subsequent mortality, the focus on economic recovery has to be taken seriously. What is worrying is that 193 countries appear to be fighting the virus and the pandemic in 193 ways as if the virus requires visa permits which can be denied and the walls can stop the virus. A global pandemic requires a global response with a clear inter-linked strategy for health , 17, 103Publicly available datasets were analyzed in this study. These data can be found here:https://databank.worldbank.org/source/jobs/Series/NY.GDP.PCAP.PP.KD).GDP per capita: World Bank, International Comparison Program database (https://www.ilo.org/shinyapps/bulkexplorer46/?lang=en&segment=indicator&id=UNE_2EAP_SEX_AGE_RT_A).Unemployment rate: ILO .IHME. Global Health Data Exchange (MB developed the conceptualization and statistical analysis, and wrote the main findings in relation to the literature. DB wrote portions of the introduction, relation to psychiatry and mental health services, policies focused on underprivileged populations and The Way Forward, and wrote the abstract and edited the full manuscript. All authors contributed to the article and approved the submitted version.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.


In the last decades, the staggering progress in nanotechnology brought around a wide and heterogeneous range of nanoparticle-based platforms for the diagnosis and treatment of many diseases. Most of these systems are designed to be administered intravenously. This administration route allows the nanoparticles (NPs) to widely distribute in the body and reach deep organs without invasive techniques. When these nanovectors encounter the biological environment of systemic circulation, a dynamic interplay occurs between the circulating proteins and the NPs, themselves. The set of proteins that bind to the NP surface is referred to as the protein corona (PC). PC has a critical role in making the particles easily recognized by the innate immune system, causing their quick clearance by phagocytic cells located in organs such as the lungs, liver, and spleen. For the same reason, PC defines the immunogenicity of NPs by priming the immune response to them and, ultimately, their immunological toxicity. Furthermore, the protein corona can cause the physical destabilization and agglomeration of particles. These problems induced to consider the PC only as a biological barrier to overcome in order to achieve efficient NP-based targeting. This review will discuss the latest advances in the characterization of PC, development of stealthy NP formulations, as well as the manipulation and employment of PC as an alternative resource for prolonging NP half-life, as well as its use in diagnostic applications. Nanotechnology for years held the promise of radically improving detection and treatment of many different diseases. The concept of using nanomaterials to improve the delivery of drugs and enhance the diagnosis of pathologies has driven biomedical research for decades. These efforts have brought to the development of a wide swath of nanovectors, with highly heterogeneous compositions and applications. However, despite the development of countless nanovector iterations, only a very small fraction of these platforms successfully reached the clinic Ventola, . This hiIn order to solve these issues, it is paramount to achieve a better understanding of the interaction between NPs and the biological environment they are exposed to. In the sixties, Vroman discovered that when a synthetic material, including NPs, comes in contact with any biological fluid, it becomes quickly covered by resident proteins  and PC protein folding  in CD-1 mice, and the blood was recovered after 10 min. Relevant differences have been found in the conformation of PC-composing proteins. The in vitro PC showed a high presence of fibrillar proteins covering homogeneously the surface liposomes. Conversely, in vivo assembled PC had a less homogeneous and non-fibrillar pattern. Notably, in vivo PC was much more diverse in its composition and showed more protein amount than the in vitro condition. Similarly, the study by Hadjidemetriou et al. , although this phenomenon was not observed in the patients involved in the study. Perhaps the most important result of this study is due to the observation that the most present protein in the PC was the CS0DD006YL02 protein. Remarkably, this protein was not detected in the control plasma derived from the same patients. The appearance on the liposome's PC could be due to the high affinity of this protein for the NPs, despite its extremely low amount in the blood. This PC-mediated enrichment could make this molecule more detectable, since the high noise from heavier molecules present in the blood at higher amounts is reduced.Composition of the PC can be quite different if NPs are exposed to the biologic fluids u et al.  evidencein vitro was investigated under different flows mimicking those present in vivo. Indeed, blood velocity in humans spans over three orders of magnitude (from 0.03 to 30 cm s−1). Although the PC is per se enriched in some proteins from the original biologic fluid, the increase in flow rate increases or decreases the amount of specific proteins. The proteins enriched at higher flow rates  interestingly were characterized by more structural flexibility, suggesting a conformational contribution to stable binding to NPs. Some proteins, however, were not influenced by the flow rate, demonstrating particularly high affinity for the NPs. By alternating the incubation with different medium , Bonvin et al. highlighted that PC composition was substantially different, depending on the order of NP incubation with blood and lymph. Moreover, especially at lower flow rates, PC retained the fingerprints of the first compartment encountered, suggesting the possibility of PC evolution across the organism, as a function of the administration route and the biological compartments encountered.Static and dynamic  conditions were demonstrated to be critical in determining the protein composition in the PC compared even with the biologic fluid. For instance, in the study by Bonvin et al. , the PC PC forms almost immediately onto the NPs after exposure to biological fluids, but its composition can vary over time. The assessment of PC over time allows also to get an insight of the kinetics of protein binding and its changes over time. More specifically, some proteins tend to decrease or increase over time, while others have only a transient increase (or decrease). Hadjidemetriou et al. assessed PC composition over time of PEGylated liposomes loaded with doxorubicin  could follow different paths: transfer from an extracellular fluid to another, transmembrane migration, and interactions with different cell populations before arrival to their destination. In the simplest scenario, NPs are administered IV and come in contact first with blood and then with lymph before reaching their target. On the contrary, NPs administered subcutaneously follow the reverse order of exposition. When NPs reached the blood, their fate may depend on the formed PC. Although it seems to be established that a PC is highly enriched in proteins such as complement factors, immunoglobulins, and coagulation factors is indicative of NP short blood circulation time and quick removal from circulation, the actual efficiency of these proteins working as opsonins for phagocytic cells is not well-established. In the study by Saha et al.  can alter the intestinal mobility, permeability, and microenvironment composition over time. Actually, there are very few studies regarding the GIT PC formation and composition of orally administered NP formulations . For this reason, some studies also focused on the evaluation of PEG on the NPs targeting the efficiency of different CNS cell populations. Jenkins et al. demonstrated how the use of PEG to coat magnetic NPs reduced their uptake from CNS immune cells but at the same time also reducing the uptake from neurons . However, little is known about how the PC of NPs changes when they cross this hurdle. One of the few studies on this topic is provided by Cox et al. . In thisMany different techniques are available for the analysis of the composition and thickness of the PC. However, none of these experimental approaches is exhaustive, and thus, the combination of different analytical approaches is essential in order to characterize PCs. The following section is just an overview of the main techniques employed in the most recent studies on PC, and the interested reader is directed to specialized reviews  and transmission electron microscopy (TEM). DLS allows for the measurement of the NP hydrodynamic diameter. The increase in NP diameter after their incubation with a biological medium is normally attributed to the protein adsorption onto the NP surface. By calculating the difference between the original NP diameter and the PC–NPs diameter, the thickness of the PC may be estimated. However, the apparent increase in NP hydrodynamic diameter is several times than that of the original NP size, meaning that other mechanisms can contribute to this increase . DLS allows also for the estimation of zeta potential (ζ), which is dependent on the NPs' surface charge. Normally, after NP incubation with proteins, the zeta potential tends toward a value of a few mV below zero, independent from the NPs' original charge. This ζ shift is often attributed to the protein on the surface of the NPs.In the case of TEM, the protein corona presence is detectable directly by evidencing the presence of an electron-dense “halo” of proteins surrounding the NPs. However, this technique is not free from caveats, since the sample preparation, itself, can have effects on the PC causing protein destabilization. A relatively milder approach is to use Cryo-TEM, which allows the visualization of PC in its native state through extremely quick freezing of the sample. These techniques, however, have low throughput and cannot be used routinely on many formulations.Besides thickness, the protein amount in PC is another parameter to evaluate. Among the simplest approaches available is simple protein quantification using colorimetric assays (Braford or BCA) that give the amount of protein in mass, but without any information regarding their composition. However, it is important to consider the possible interference of NP components on the yield of this colorimetric assay. This limitation could be overcome by creating adequate calibration lines of standard protein concentrations in the presence of particles.A slightly more advanced technique relies on SDS-PAGE or two-dimensional gel electrophoresis (2DIGE) coupled to densitometric analysis. This analysis is easy, quick, and cheap and allows for the resolution of proteins depending on their molecular weight. The additional information this approach provides is evidencing the relative abundance of proteins at different molecular weights that can suggest qualitative changes in the PC composition. Despite some studies trying to identify a protein based only on the molecular weight, this does not provide true evidence of the protein's identity. Furthermore, SDS-PAGE is not very sensitive and provides only a rough estimation of the molecular weight. Gel-based separation allows for better confidence in single protein identification when coupled to mass spectrometry or Western blot analyses.Mass spectrometry-based proteomic analysis is the most useful technique to obtain a confident protein identification  allows to obtain several information and calculate the binding constant of a protein to the NPs, the protein to NP stoichiometry, and the NP surface area that each one occupies. However, this analysis does not allow for the calculation of such precise parameters for more than a single protein at a time, making its application not very easy to correlate to the complex array of molecules present in biologic fluids. Another option is based on the use of surface plasmonic resonance (SPR) probes with the immobilized proteins on their surface. These probes can change their optical proprieties depending on the adsorption of NPs on their surface and then permits to accurately measure the NP–protein interactions in real time and even under flowing conditions  that permit to highlight changes in the percentage of specific structural components  after incubation with NPs, indicating the change in protein conformation and evidences of its denaturation. More recently, conformational alterations have also been predicted and simulated in silico. This strategy is quite elegant and allows for a complete assessment of the chemical nature of the interaction as well as for the protein affinity and behavior on the NP surface. However, this approach is also quite difficult, and the correlation between simulated conditions of interactions and reality is not always straight forward  rely on conformational changes in order to activate their respective signaling cascades, and otherwise, some In the last decades, the understanding of PC as one of the primary factors contributing to NP destabilization and quick clearance after injections led to the development of many nanomaterials with the specific focus of reducing or slowing down the PC assembly, thus, improving NP biodistribution. In the present section, an overview of the latest advances regarding these materials is presented.Although PEG has been considered for many years as the gold standard of stealth-inducing materials and is still used for the production of stealth drug delivery systems . This study is of importance since it demonstrates that NP architecture, itself, is a critical component in their immunogenicity.The issue of production of anti-PEG immunoglobulins as stated above is a major hurdle in the chronic and widespread use of this polymer as stealth-inducing material. However, the mechanism of clearance dependent on the presence of anti-PEG antibody is only partially understood. A recent study by Grenier et al.  focused de facto reducing their targeting efficiency  have recently gained a lot of attention as a novel stealth-inducing polymer thanks to its ease of synthesis, biocompatibility, and biodegradability, with high efficiency in prolonging NP circulation  has been employed. By analyzing the uptake by tumor cells and macrophages, the authors established that the optimal formulation was represented by PEG2000 NPs coated with cRGD (at a density of 75%). The uptake by macrophages was particularly reduced, however, by NPs coated with PEG10000. For all formulations, the presence of serum during the incubation substantially hindered NP uptake in all cases, although with some variability among formulations. Finally, the presence of PC showed overall homogenous presence of proteins with sporadic fluctuations in the total amount but with overall comparable profiles. Although this study does not provide a conclusive solution on how to optimize targeting while avoiding phagocytosis, the use of a wide range of combinations and the considerations of multiple variables in NP design offers an interesting insight on PC-informed NP design approach. Furthermore, it was also demonstrated that NPs in the presence of serum are internalized by cells by different endocytic/phagocytic pathways compared to the serum-free conditions, especially shifting the uptake by macrophages from phagocytosis to clathrin-dependent endocytosis.Although the stealth-inducing materials can provide a great benefit for NP pharmacokinetics and improve their tumor accumulation through passive targeting, the uptake of NPs by the target tissue is often slow and non-specific. In order to overcome this, the use of active targeting moieties on the surface of NPs has gained attention. These moieties represent a wide swath of chemically heterogeneous molecules that range from small compounds such as folic acid, to big proteins such as antibodies and soluble proteins. They are selected in order to bind specific receptors present on the target cells, thus increasing the endocytic uptake of NPs. However, since these moieties are exposed onto the surface of NPs, they also modify the interface identity and its interaction with the biological environment they are in. Thus, their effect on the PC assembly and composition must be considered since it adds another layer of complexity to the design of NPs. The use of different moieties has been extensively discussed in other works and goes beyond the scope of the present paper  and define their intercellular and molecular interactions, providing an inherent initial biologic identity. However, when thinking about the normal path of a NP formulation after injection, the first environment it meets is blood. Thus, using cell membranes and membrane proteins from circulating cells appears an ideal solution in order to bestow NPs with long circulation by camouflaging them as biological components normally present. The use of these cells types allows the NPs to interact with the proteins present in the blood similar to how the cells do, and thus, by separating the NPs from their surroundings, they can provide not only colloidal stability but also avoid opsonization and the production of anti-NP immunoglobulins that could result in quick NPs clearance and potentially C activation-related pseudo allergy.One of the most well-established biomimetic approaches to increase NP circulation time is coating them with cell membranes. The use of entire cell membranes allows the NP surface to Following this concept, a wide array of formulations was produced by using a handful of cellular sources: red blood cells (RBCs), platelets, leukocytes, and cell-derived exosomes. RBC-coated NPs are among the first biomimetic formulations employed  normally present on leukocytes. Theoretically, leukosomes, through these receptors, could bind circulating immunoglobulins not through their antigen-recognizing variable portion, but through the constant domains. This could present the immunoglobulins activation as primers for complement activation and opsonization by the MPC de facto making them beneficial for the biodistribution of leukosomes. This intriguing mechanism underlines once again the ambiguity of function of certain protein classes composing the PC, since not only their presence but also their conformation and orientation could have an important impact on the overall final impact of PC on the fate of NPs.Only a few studies have focused on the investigation of the PC of biomimetic nanosystems. An example among these is the recent work from Corbo et al. . In thisin vivo has been demonstrated to prime the production of anti-virus immunoglobulin that triggers their quick clearance from circulation. To overcome this critical hurdle, more studies on the molecular composition of viral surface could be useful to distinguish among the components responsible for their stealthiness while removing the potential immunogenic motifs.Viruses have been considered an inspiration in the design of drug delivery nanovectors since the inception of this field of research  coated with different stealth-inducing biologic materials: alginate or hyaluronic acid  . This phenomenon could be explained by the differential processing of TMCs and SA after phagocytosis by macrophages, as shown by confocal microscopy imaging after in vitro incubation of SA-TMC onto RAW 264.7 cells. Indeed, it was demonstrated, in fact, that after phagocytosis, TMC NPs were trafficked toward the lysosomal compartment (and so toward antigen processing), while the conjugated SA followed a quick recycling path back to the plasma membrane. This study is a remarkable example of how the proper assessment of the biological fate of stealth nanosystem can give important insights in the actual mechanism of immunogenicity of a drug delivery vector.The Another interesting example of how the biologically informed design of a nanomaterial can achieve a great improvement in its interaction with the biological environment was given by Magro et al. . In thisin vivo experiments, PLGA-PEG-Mal NPs had a circulation half-life comparable to PLGA-PEG, but after multiple administration, the production of anti-PEG immunoglobulins was lower than for PLGA-PEG NPs. Furthermore, PLGA-PEG-MAL demonstrated more efficient targeting in tumor-bearing mice. This is most likely, thanks to a higher uptake of albumin by tumor cells.Following the idea of some commercially available albumin-based drug delivery systems , Li et al. formulated a novel formulation of PLGA NPs coated with PEG presenting on its surface-reactive maleimide moieties  and had higher therapeutic efficacy than PEGylated NPs. This is a true demonstration of how the advanced manipulation of the PC can provide new stealth and active targeted nanovectors that show improved profile even when compared to the polymers considered as gold standard for NP long circulation.Another recent work by Oh et al.  further Other studies have achieved similar results using non-covalent NP coating with serum proteins. A study by Yeo et al.  demonstrin vitro and in vivo is the strategy of molecular imprinting . Moreover, there is not a standard workflow that could be used to obtain more systematic PC information that could be more easily comparable among different studies. Although the use of in vivo models in conjunction with proteomic analysis can greatly enhance the quality and amount of the obtainable information, the use of animals exclusively for PC assessment could be quite demanding in terms of logistics and funding, not mentioning the ethical implications. Furthermore, the precise indication of all experimental settings and the implementation of standardized experimental guidelines could further harmonize the PC characterization. Despite the high interest in the study of PC relevance in NP platform development, proteins are not the only biological molecules interacting with nanovectors. Recently, some studies shed light on the binding of lipids on NPs, in particular, lipoproteins present in plasma.In this review, the difficulties in the PC investigation were evidenced by presenting all the known NPs and experimental variables that can alter the PC composition. Despite the complexity of this field of study, still many studies rely on simple vice versa, larger (and less dense) lipoproteins interact in lower numbers with NPs. Interestingly, lipoproteins were shown to interact with NPs more strongly than apolipoproteins, indicating the role of lipids, themselves, in determining the lipoprotein affinity. Furthermore, this study evidenced that there is a significant fraction of lipoproteins disintegrating on the NP surface, leading to direct covering of NPs by lipids. This was further reinforced by the high NP retention of cholesterol after multiple centrifugation. Importantly, it was demonstrated that after incubating NPs with pure lipoproteins, their uptake by RAW264.7 macrophages was highly reduced. Taken together, all these data underline the importance of including not only proteins in the study of NP coronae but also the potential utility in exploiting lipoproteins as a novel clocking mechanism to increase NP circulation time, thus, offering a new strategy to improve their targeting capabilities. This innovative concept is considered a broader view on NPs' biological interactions with molecules, and often defined as “biomolecular corona,” since it includes proteins, lipids, sugars, and other metabolites ; furthermore, their complex structure and composition still poses severe problems regarding the reproducibility and reliability of their proprieties. Following these considerations, none of these approaches to stealthy NP formulations are ideal and can achieve ideal behavior and at the same time satisfy the need for scalability that the clinical praxis demands. Perhaps the combination of the finely tuned chemical synthesis and of the biocompatible and versatile biologics could converge and generate a new, holistic paradigm of stealth NPs design.The potential coating of NPs with an artificial PC has also an amazing potential for increasing the circulation time of nanomaterials, and even providing natural active targeting moieties, using purified (and perhaps even recombinant) proteins, and thus avoiding the complications of using entire membrane proteins or a wide array of membrane proteins. This approach could allow to produce finely tuned highly reproducible biomimetic formulations. Another fascinating approach could be the use of patient-derived purified disopsonins to create a personalized coating for each patient on chemically reactive NPs, resolving any potential issue of immunogenicity that haunts many biomimetic formulations. The future nanomaterials could even be composed entirely of disopsonin proteins, not different from the already currently available albumin-based nanovector Abraxane™. However, these new horizons heavily depend on the bottleneck of our limited understanding of which proteins composing the PC are the most critical in improving NP biodistribution.Regarding this limiting factor, many studies on the PC are in several cases contradictory. For example, immunoglobulins are often associated with poor NP stability and quick clearance from circulation. However, some studies also demonstrated how immunoglobulin are negatively associated with NP uptake from macrophages and even how they can work as disopsonins by binding to the FcR on NPs presenting this receptor. Thus, immunoglobulins enhance NP clearance only if they can bind to specific epitopes on the NP surface, thus, activating and making NPs visible to immune cells. If Igs, however, bind non-specifically or not through their antigen-recognizing domains to the NP surface, it is likely that they work as any other protein of the same size and surface charge, thus losing their immunological relevance.in vitro and in vivo investigation, with attention to their translational potential. Furthermore, extensive study of currently approved nanovectors in clinical setting could provide invaluable information on in vivo human PC. The analysis of PC should take great advantage from the “omics” techniques, which provide unprecedented amount of information on such complex samples. Finally, an extensive and standardized panel of the PC assembly conditions and results should be provided, in order to make the studies more easily comparable and consistent. This panel should include already well-established biological tests such as the uptake and activation by macrophages and complement activation. All these changes are complex and require the collaboration of all the major experts on the PC field in order to unlock the staggering complexity of PC overcoming the contradictory nature of the current results and thus create a coherent, comprehensive, and predictive model describing the relevance of PC in NP stability, biodistribution, and safety.In conclusion, our understanding of the PC composition, relevance, and manipulation has substantially expanded in the last years. However, the experimental difficulties in its characterization and its over-simplified interpretation have led to only partial and, in some cases, potentially skewed understanding of the role of different protein classes that are present in the PC. In this perspective, it is necessary to develop in the future harmonized techniques for the study of PC assembly and its analysis. These techniques should cover both RR: writing the original draft with support from SC. PC and SP: revising the article. MA: conception and design.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.


Fish production has been practiced since ancient Egypt and China. It has become a fast-growing agricultural sector that provides animal protein for most people globally. While China is the leading country in the world, Egypt and Nigeria stand on the top in Africa. The overall fishery production potential of Ethiopian water bodies is estimated to be 94,500 tons per year, while the actual production is 38,370 tons. Despite more water bodies and more fish diversity in the region, fish production and marketing is very low. This review is undertaken to assess the main factors affecting fish production and the marketing chain in Gambella region. Despite the known water and fish potential of the region, fish production is very low. Major factors contributing to a reduction in fish production in the region include inefficient fishing gears, poor transportation access, poor postharvest handling, low price at the landing site, and improper market place. Drying is the predominant postharvest technique and fishing methods are of a subsistence basis. All the fishing activities take place in the natural environment, and aquaculture is not yet established. Enough modern and efficient gears need to be made available. Other modern postharvest handling techniques need to be introduced to ensure a longer shelf life of fish after harvest. Infrastructures need to be constructed to access all water bodies in the region. Because the region has such water resource potential and incredible fish species diversity, the aquaculture needs to be established and popularized. Traceability needs to be adopted in the region to prevent food-borne diseases. Based on this paper, the government and other stakeholders could develop policy considering the issue of the fishery status of the region. Fish farming has been practiced in different parts of the world, particularly East Asia, China, Europe, Canada, Africa, and developing countries like Nigeria . It has With more focus on the nutritional value of food commodities, fish is acknowledged as a major nutrient-rich animal food source for a significant proportion of the nutritionally vulnerable people, overshadowing that of most of the terrestrial animal foods. In the last decade, of the 30 countries where fish contribute more than one-third of the total animal protein supply, 22 are Low Income and Food Deficient countries (LIFDCs) .The contribution of fishery activities to national economies is multifaceted. In addition to supplying food, the fishery sector contributes to gross domestic product (GDP), provides livelihoods for fishers and processors, is a source of hard currency, and boosts government revenues through fisheries agreements and taxes .In boosting the economy, world per capita fish supply reached a record high of 20 kg in 2014 . While tAquaculture is still developing in Africa and is mostly concentrated in a few countries but already produces an estimated value of almost US$3 billion per year . The valIt is wise to put forth the distinction between these two capture fisheries aquatic ecosystems, marine and inland ecosystems, as they influence the fish species being targeted. The inland fishery of Africa is estimated to contribute to about 2.1 million tonnes of fish per year. It represents 24% of the total world fish production from inland water bodies . In EthiThe overall potential yield of fish in Ethiopian water bodies is estimated to be 94,500 tons per year on average , 9. HencAs the presence of sufficient freshwater bodies may signify indirect fish availability, Gambella is endowed with several inland water resources including rivers, lakes, reservoirs, ponds, and huge floodplain areas but contributed far less to national fish production and marketing. From the literature, Gambella is the region with the most diverse fish species in its water bodies but rarely reported for its fish production and marketing. Therefore, this review is carried out to assess the major factors which could possibly contribute to the low fish production and how the fish market is oriented in the region.Fish consumption varies greatly depending on the quality and quantity of fish supply available for consumption. Ethiopians have no tradition of consuming large quantities of fish, rather highly committed to rearing and consuming farm animals. The fact that most Ethiopians are not actively involved in fish consumption may also be a reason for them to have little participation in fish production. It is true that when a product is no longer demanded by the consumers (customers), the trader would not supply it anymore and shift to other products in demand. Knowing the nutritional and economic value of fish, for how long will the tradition of low fish consumption and demand continue?In religious perspectives, the Ethiopian Orthodox Church undergoes several fasting periods when they refrain from meat consumption and consider fish as good enough to be consumed . In thosOreochromis niloticus, Clarias sp., Polypterus bichir, Heterotis niloticus, Gymnarchus niloticus, Malapterurus sp., Lates niloticus, Alestes spp., Hydrocynus spp., Mormyrops spp., Bagrus spp., Barbus spp, and Labeo horei. Moreover, Hussien et al. [Regardless of the big rivers and lakes found in the country, a Baro-Akobo basin is the most diverse in terms of fish diversity and its floodplain is the largest one in the country. Even though Baro River is recorded as the most diverse in fish species throughout the country, its contribution to national fish production is less documented. Although local people exploit the river system on a subsistence basis, they utilize it to fulfill their daily food requirements. Getahun  reportedn et al.  reportedLocal fisher's cooperatives and fishers being the sole exploiters, Baro River, Gilo River, and some other smaller wetlands in the floodplain are the major places where fishing activities are largely intensive. The catch estimates from rivers around Gambella is 5,000 tons/year, whereas the actual fish production potential is about 12,000 tons/year . In natiFishing is generally in the subsistence scale in this river system where fishes and fish products are chiefly used for household consumption, whereas a small amount is sold at local markets to obtain additional income. The majority (64.6%) of the surveyed fisher respondents who have access to the market mentioned that their usual clients were consumers and few (35.4%) of the respondents sold their products to the retail shops and hotels . BecauseThe amount of fishes produced in a certain water system is determined relative to the potential the water system has to produce fishes. The fish production potentials of the main rivers of the Baro-Akobo Basin alone  were estimated to be 3,720 tons per year . HoweverThe efficiency and modernity of the fishing materials and equipment determine the production status of a particular water body. The fishers in the Gambella region use different and traditional gears with more than 15 types. The usage of these gears tends to vary with seasons, methods of fishing, and the materials they are made of. Some modern fishing gears such as seine nets, hook, and line and cast net were supplied by NGOs operating in the region and are being used by individuals and fisher cooperatives , 16. ButGambella experiences two conspicuous seasons: the dry season and wet season. Since the region is located in the lowland floodplain of the country, there is a regular incident of the flood that can cover the whole floodplain and displace most local residents in the lower elevation in the wet season. Because of this flood, most activities become disrupted and put into a halt in the wet season, including fishing. The seasonal halt in fish production implies that the fishing activities are not much intensive, and people do not exclusively utilize fish resources. In contrast to the nations where fishing is used to secure a huge amount of funds, there is no what so-called seasonal close down in fishing.The survey conducted by Abegaz et al.  intervieBecause of its high protein content, fish is one of the most perishable foods that can be spoiled easily if not properly preserved, particularly in tropical and subtropical climates . Fish caThe most common form of fish preservation technique practiced in Gambella is drying. Sun drying is the simplest way of preserving fish and is practiced not only in Gambella but also in some Rift Valley lakes where fish are caught locally . FishersDeep freezing and cold rooms are also used in some cases by Fish Production and Marketing Enterprise centers in the Gambella region. Even though there are some modern preservation facilities like refrigerators for temporary fish collection, they do not have enough power supply to keep the facilities function properly. The problem is intense because most fish retail shops, fish collection, and storage facilities do not have backup diesel generators . There iCapture fishery involves the catching of valuable aquatic organisms from their natural environment. All the fish utilized in the country are collected from the wild by subsistence means. Though Gambella is known for its remarkable fish diversity in its water bodies, it contributes little to the national fish consumption. Most of the fishery resources consumed in the big cities and towns in Ethiopia are captured from the Rift Valley lakes (40%) and Lake Tana (50.2%) . SubsistSo there is an urgent need to establish aquaculture in the country for farming valuable aquatic organisms under controlled artificial environments to replace the declining capture fishery. There is no report about Aquaculture in the Gambella region. Because of the region's water bodies and fish potential, it is in the mind of fisheries experts to establish aquaculture in the region. Therefore, Gambella is regarded as “the dreamland for aquaculture,”Escherichia coli, African swine fever, highly contagious diseases such as avian flu in poultry, bovine spongiform encephalopathy (BSE) and foot and mouth disease in livestock, presence of dioxin, and microorganisms like Salmonella, Norovirus, Campylobacter, Listeria, Clostridium [Food safety has become a growing concern for citizens of many countries where they expect safe and nutritious foods. Today, food safety is a worldwide concern due to a number of food safety scandals. Outbreaks of diseases such as stridium , and CorFor the better wellbeing of the people, a reliable traceability technique is needed to inspect all the food products, including fishes being supplied. Good traceability in food supply chains has the potential to reduce risks and costs associated with food-borne disease outbreaks, product recalls, maintaining consumer, or market confidence in product , 25. In Improving traceability at the supply chain level can potentially reduce the costs to downstream actors in monitoring the activities of upstream steps , 25. ReaTraceability implementation is a tedious task. Thus, it requires automated data collection to reduce much of the time and expenses required for data processing and maintenance. Gathering information for large operations manually is time-consuming and leads to risks of recording the information incorrectly. For example, errors occur in 36% of consumer packaged goods orders according to a study by the Grocery Manufacturers Association (GMA) in the United States . Such erMoreover, among many tools and techniques developed,  suggesteEnsuring traceability through the food chain can be accomplished by careful planning, taking the time to gain consensus among the food operators, and gaining the trust of the consumers. In order to gain consumer trust in the traceability system as a whole, the traceability system in place must meet the set standards.To have a common understanding about food traceability among food business operators is imperative when agreeing to the introduction of a system through the food chain. Equally as important is ensuring the consistency of the food traceability system implemented by each food operator and making effective connections among all the systems.Vibrio, are frequently associated with the consumption of raw and undercooked shellfish [Molecular studies will continue to clarify the taxonomic status of seafood-borne pathogens and their relationship to one another. Outbreaks of certain human pathogenic bacteria, such as members of the genus hellfish .Though Baro-Akobo basin has the most diverse fish species, it contributes little to the national fish demands.The major constraints that reduce fish production in the Gambella region include inefficient fishing gear, poor transportation access, lack of fish handling facilities, and poor postharvest handling.Drying is the predominant postharvest handling technique practiced in the region.Major marketing constraints include low prices at the landing site, poor road access, high transportation cost, improper market place, lack of cold storage, and poor power supply.The fishing methods used in the study area are predominantly traditional and of a subsistence basis.All the fishing activities in the region take place in the natural environment, and aquaculture is not yet established.Insufficient institutional and management capacity, limited resource allocation and investment, poor policy and regulatory framework, and insufficient value chain and fish marketing infrastructure are some of the cross-sectoral challenges affecting fisheries in Ethiopia, particularly the Gambella region.Traceability is a concept utilizing a variety of tools and advanced technologies in assuring public health by inspecting food before being used.The most important benefit of traceability is the improvement of supply chain management. Other benefits include an increase in the ability to retain existing customers, product quality improvement, product differentiation, and reduction of customer complaints.Enough modern and efficient gears need to be made available in the regions to be used by the fishersEnough power supply needs to be installed in the Fishery Production and Marketing Enterprise collection centers and other postharvest handling techniques need to be introduced in the region to ensure a longer shelf life of fish after harvestRegional governments need to construct infrastructures to access all water bodies in the region and stabilize the current security problem faced by the fishersBecause the region has such water resource potential and incredible fish species diversity, aquaculture needs to be establishedTraceability needs to be adopted and effectively implemented worldwide, including developing nations to ensure the safety of the public