Preventive subcutaneous treatment of severe hemophilia A with bispecific antibodies that mimic the action of coagulation factor VIII (FVIII) is emerging as an effective alternative to replacement therapy with intravenous administration of FVIII concentrates, either derived from plasma or produced by biotechnology. Access to this innovative therapeutic approach for a growing number of patients worldwide increasingly appears to be a priority public health strategy. Inclusion of FVIII mimetic bispecific antibodies on the World Health Organization essential medicines list would contribute to health equity in lower-income countries. •New hemophilia agents called bispecific antibodies mimicking factor VIII are important treatments.•The new medicine emicizumab is one and is effective administered under the skin instead of intravenously.•Wider access to these antibodies worldwide appears to be a public health priority.•Granting of WHO essential medicine status would lead to more equity for low-income countries. Hemophilia A is characterized by a complete or partial deficiency of blood clotting factor (F)VIII. The consequence is the occurrence of abnormal bleeding episodes. In patients with complete or near-complete FVIII deficiency, bleeding may occur spontaneously, mainly in the joints and muscles. These bleeds (sometimes a single episode) usually lead(s) to irreversible joint destruction, causing pain and disabling functional limitations, the main complications of hemophilia .The classic treatment for hemophilia A is replacement therapy to compensate for FVIII deficiency . It is bHowever, many limitations of these treatments remain: the burden of venous access, which is particularly problematic in young infants and children and some older patients; the short half-life of the administered factors imposing frequent injections  ,4; the fSome limitations of replacement therapies may be resolved by exploiting the cofactor properties of FVIII. The main function of the latter is to catalyze the activation of FX by FIXa . This roThe therapeutic role of emicizumab has been studied and demonstrated in a large program of HAVEN clinical trials involving children and adults with hemophilia A, with and without inhibitors, treated weekly or less frequently, ie, every 2 to 4 weeks. These studies demonstrated the hemostatic efficacy and safety of emicizumab, with low rates of breakthrough bleeding episodes . Rare thWe propose that emicizumab should be considered as an essential medicine by the World Health Organization (WHO) to facilitate adoption in lower-income countries where it would be very useful. The WHO Model List of Essential Medicines was created in 1977 as an important step toward ensuring more equitable access across socioeconomic strata . While iEmicizumab is currently registered and available in many countries . AlthougFor all patients with a severe hemophilia phenotype, the treatment explicitly recommended by the World Federation of Hemophilia (WFH) Treatment Guidelines is prophylaxis, ie, the regular and preventive administration of a treatment to prevent spontaneous joint bleeds . HoweverEven in well-resourced countries, and despite multiple initiatives, meeting the requirement that 100% of patients are on prophylaxis and have virtually no spontaneous joint bleeds is proving to be an elusive goal. In addition, even patients treated with full dose prophylaxis who have no clinically detectable bleeding episodes often develop ankle arthropathy, a sign of uncontrolled subclinical bleeding due to inadequately low FVIII trough levels ,18. It rAlthough emicizumab is neither a cure nor a monotherapy, its multiple properties make it a first-line treatment for almost all patients, potentially including newborns , with heIn this context, emicizumab and other FVIII mimetic bispecific antibodies under development  should b


With respect to public health, the insight that many modern human pathologies  result from mismatches between the ecologies in which we evolved and our modern environments has important implications for disease prevention. Life-history evolution can also shed important light on patterns of disease burden, for example in reproductive health. Experience during the COVID-19 (SARS-CoV-2) pandemic has underlined the critical role of evolutionary dynamics  in predicting and managing this and future pandemics, and in using evolutionary principles to understand and address aspects of human behavior that impede biomedical innovation and public health . In conclusion, greater interdisciplinary collaboration is vital to systematically leverage the insight-generating power of evolutionary medicine to better understand, prevent, and treat existing and emerging threats to human, animal, and planetary health.Evolutionary medicine – i.e. the application of insights from evolution and ecology to biomedicine – has tremendous untapped potential to spark transformational innovation in biomedical research, clinical care and public health. Fundamentally, a systematic mapping across the full diversity of life is required to identify animal model systems for disease vulnerability, resistance, and counter-resistance that could lead to novel clinical treatments. Evolutionary dynamics should guide novel therapeutic approaches that target the development of treatment resistance in cancers (e.g.,  The Quarterly Review of Biology  applies insights from ecology and evolution to inform, direct, and ultimately improve biomedical research and public health and clinical care. Williams and Nesse’s pioneering 1991 review in  Biology , 3. Whil Biology , 5, a raHere we describe the biomedicine research areas in which evolutionary approaches continue to spark transformational innovation  and propCrucially, the systematic study of the full diversity of life exposes the invaluable yet unrecognized model systems that surround us. By focusing on the dynamic interdependence of biological organisms and environments, evolutionary medicine recasts pathology and the body’s countering mechanisms in terms of resistance and counter-resistance. Without an evolutionary framework, these insights – and the potential gains for patients – would go unrealized.Characterizing the almost inevitable evolution of resistance to medical therapies – whether anticancer drug resistance among cancers or antimicrobial resistance among pathogenic microbes – is one example of how evolutionary perspectives are transforming our understanding of the natural history of disease itself . An evolEvolutionary medicine is not focused simply on improving patient health though better clinical care; it also has the potential to benefit several important areas of public health. The recognition that many modern human pathologies result from mismatches between ancient ecologies, in which much human physiology evolved, and our modern environments has recast health and disease in a broader evolutionary context. Life-history evolution emphasizes the understanding of historically important developmental trajectories and environments to contextualize mismatches that may create pathology. Insights from evolved life-history traits and environmental mismatches have important implications for public health policy.We must also apply lessons from evolutionary medicine to prepare ourselves for a future life with COVID-19 and other novel zoonotic diseases. Evolutionary models are essential for both predicting and managing pathogenic outbreaks. Also, experience gained during COVID-19 has underscored the fundamental importance of human behavior to the success of medical and public health responses to pandemics. For example, human resistance to the use of novel biomedical innovations – manifested as vaccine hesitancy – has undermined the effectiveness of the extraordinary mRNA vaccines against COVID-19. Thus, to properly apply new ecological and evolutionary insights we must understand these forms of human resistance and how to overcome them. Key to this is recognizing that natural selection works to maximize lifetime reproductive success not survival, and that humans are extremely heterogeneous – meaning that “one-size-fits-all” solutions will not address any substantial problem, including vaccine hesitancy.The following forward-looking sections explain how ecological and evolutionary approaches have tremendous – and as yet unrealized – potential for improving human health and wellbeing.Evolved physiological adaptations offer some of the most remarkable examples of biodiversity found in the natural world . ContainOnly recently has it been possible to identify strategies within the physiological systems of a broad array of other species to counter complex human pathophysiology. Several factors have limited this quest. First, researchers and professionals in human health may have little awareness of the phylogenetically widespread vulnerabilities or resistances to so-called “human” diseases – infectious or noncommunicable – existing in nature . InadequThe reduction in noncommunicable diseases through improved diet, increased activity, and a decline in disease-promoting practices (such as smoking) has provided strong evidence for modern human culture as a primary “cause” of disease . This emUncovering differences in species-specific vulnerability is the first step in identifying natural animal models that can provide a blueprint for improving human health. The challenge, however, is that the absence of disease in an individual animal may reflect nothing more than a lack of environmental exposure. Vulnerability is a hidden trait that becomes apparent only when disease emerges, often because of an individual’s unique genetic profile and history of exposure. Despite the challenges in ascertaining the relative disease vulnerability across and between species, the effort is warranted because there may be adaptations conferring enhanced resistance or vulnerability to many diseases that collectively confer much of the global disease burden . FindingIdentifying the biological mechanisms that underlie disease resistances can provide investigators with a blueprint to generate strategies to counter these threats. However, such mechanisms must be identified before they can be studied. Thus, identifying evolved adaptations in other species  should be of significant interest to clinicians and investigators treating and studying high-impact human diseases.Future insights require a systematic approach to identifying these naturally occurring models of resistance . This caOne of the most important frontiers in cancer biology is to develop treatments and cancer-prevention strategies that support the cooperation of the normal cells in our body and help our cells detect and effectively respond to cellular cheating. These treatments and prevention strategies can help support “cheater-detection” systems that operate on every level, including cell intrinsic, neighborhood, and systemic levels. We can use insights from cheater detection in human societies  to develUnfortunately, many cancer cells can re-evolve cooperative traits that are then expressed toward other cancer cells, increasing the viability of those aggregations of cancer cells within the body . Cancer Cancer is a disease of somatic evolution, meaning that it happens because cells inside the body evolve in ways that further their own fitness interests at the expense of the body. But somatic evolution is not always harmful. Elucidating how somatic evolution can contribute to our resistance to disease is an exciting area for new work. For example, the immune system uses somatic evolution to create variants of antibodies, allowing us to respond more effectively to rapidly evolving infections . This isTreating cancer using an evolutionarily informed perspective is also about considering the evolutionary consequences of treatment for the trajectory of the cancer before and during treatment. Several approaches, including adaptive therapy and extinction therapy, are informed by the evolutionary and ecological dynamics underlying tumor responses to treatment. Both approaches reject the idea of using an anticancer drug at a high dose for as long as it works, because extended exposure to high doses selects for cells resistant to the drug used. Adaptive therapy aims to stabilize the tumor size and maintain a population of drug-sensitive cells, allowing the drug to be used for long-term tumor control . AdaptivBecause adaptive therapy and extinction therapy leverage the ability to respond to changing information about the status of the tumor during therapy, they are highly general approaches that hold the greatest promise as “universal” principles for developing new cancer therapies. It is widely recognized that the evolution of resistance poses a critical clinical problem because drug-resistant cancers can no longer be treated, leading to progression , 32–34, We are susceptible to cancer because we are multicellular organisms, but we are also highly resistant to cancer because we have undergone millions of years of evolution as cooperative societies of cells that effectively detect and respond to cellular cheating. All multicellular organisms are societies of cells operating in precarious cooperation, and an evolutionary and ecological approach can help mitigate such precariousness. This approach can also help to rebalance the evolutionary and ecological dynamics in our bodies when they are compromised by cancer cells, using approaches such as adaptive therapy and extinction therapy to leverage evolution and ecology to reduce the burden of cancer and, in some cases, even drive cancer to extinction within the body.The effectiveness with which antimicrobial drugs, insecticides, and anticancer drugs kill their targets is also their undoing. By killing drug-sensitive life, they create the conditions in which natural selection drives the evolution of drug and insecticide resistance . To simpThe conventional solution to the problem of antimicrobial resistance (AMR) is to find new chemical agents to replace those that fail. The sustainability of this drug-discovery treadmill is not obvious, especially given that resistance mechanisms are getting ever more generic (some bacteria have evolved efflux pumps that can expel drugs not yet invented), and the costs of bringing new products to market can cripple the process of translating laboratory science into approved drugs , 37. On Applying evolutionary insights to antimicrobial drug development has the potential to spark transformational innovation that saves lives. Of these, the cheapest are innovations that make better use of existing drugs. A key historical example was the discovery of evolution-proof treatment regimens for HIV and tuberculosis –43. TherSimilar theory-data interplay should determine the optimal solution to a quandary at the heart of much current practice in antimicrobial stewardship. Conventional wisdom posits that when treating patients, it is important to use drugs to rapidly eliminate cells that might mutate into resistant variants. But this conventional approach can be counterproductive in that it increases the evolutionary advantage of any resistant mutants that can survive this treatment. In almost all cases, the optimal treatment regimen  that maximizes patient health while minimizing AMR evolution has yet to be determined empirically. However, several clinical trials have revealed that treatments often continue for too long , while aA completely different approach to the resistance problem is to develop chemistries that target the evolutionary process itself. It is tempting to call these chemistries “anti-evolution drugs,” although they are not drugs in the conventional sense. Their primary aim is not to kill the target organisms (though they might do that), but rather to inhibit resistance evolution. The speed of AMR evolution, like all adaptation, depends on the genetic variation present and the strength of selection. Compounds can be identified that can reduce both genetic variation and the strength of selection.Horizontal transfer of genes from resistant bacteria to sensitive bacteria is a key means by which antibiotic resistance can spread quickly. Drugs are being developed that interfere with genetic transfer mechanisms, such as conjugation . AnotherDrugs can also be used to reduce the strength of selection for resistance. Anti-antibiotics are one approach . These cChemistries that inactivate host-derived compounds could also provide innovative resistance management. AMR selection depends on the relative competitive advantage of resistant and sensitive pathogens in drug-treated hosts. Resistant mutants have an advantage in drug-treated hosts because the drug reduces the competitive suppression that drug-sensitive progenitors would otherwise exert –61. LimiIn 2017, the World Health Organization (WHO) highlighted the threat of Gram-negative bacterial pathogens resistant to multiple antibiotics . The disvia bacterial transcription, translation, and replication; and upon formation of new phage particles, escape the cytoplasm through lysis (death) of the host bacterium. This process is then repeated by the new phage particles as they infect additional susceptible cells. These steps highlight a long-understood benefit of phage therapy: utilizing lytic viruses as self-amplifying “drugs” that target and kill susceptible cells may be more efficient than applying antibiotics that are incapable of self-amplification. Although other intracellular replication strategies have evolved in phages, these obligately lytic (or “virulent”) phages are most often developed for use in phage therapy.During its infection cycle, a lytic phage will: attach to receptor (s) on the cell surface of bacteria and deliver its DNA or RNA to the cytoplasm; undergo viral replication in the cytosol However, one obvious limitation to phage therapy is the inevitable evolution of phage resistance in the target bacteria , 71. ModPhage therapy would thus benefit from an evolutionary medicine approach; utilizing a certain phage should select for the target bacterial pathogen to evolve phage resistance, while concomitantly suffering a specific genetic trade-off that would be biomedically useful , 78, 79.epa) gene cluster of E. faecalis bacteria, where the mutants harbored altered cell-surface properties and were deficient in intestinal colonization and transmission in mice   . This de traits) , 86.Notable successes in emergency phage treatment of antibiotic-resistant infections –89 bolstAdvances in evolutionary medicine are not restricted to studying the evolution of disease vulnerability and resistance; other advances will emerge from recognizing the importance of mismatches between evolved life-history traits and the current environment. Life-history traits include growth, reproduction, and survivorship dynamics , 92. TimWomen’s reproductive life-history norms have changed profoundly in recent history compared to patterns that would have predominated throughout our species’ evolutionary past . In the We surmise premodern life-history norms based on comparisons with contemporary small-scale societies, and some information can be gleaned from the fossil record. Both methods give us only a flawed and limited estimate of our past , 100. NoBreastfeeding represents a domain in which, arguably, the largest change in life-history norms has occurred across history. Breastfeeding has been correlated with lower risk of type 2 diabetes, hypertension, cardiovascular disease, metabolic syndrome, myocardial infarction, breast cancer, and Alzheimer’s disease in mothers . TherefoOver the past century, girls have been exhibiting progressively earlier age at reproductive maturation across most parts of the globe . A biomeWhile especially good conditions can promote earlier puberty, so can especially bad conditions. Harsh environments encountered during early life have been associated with earlier reproductive maturation for girls , 109. WhLife-history trade-offs sometimes compromise disease defenses in favor of reproductive effort. An evolutionary perspective highlights the role of testosterone in modulating life-history allocations in ways that maximize fitness in various conditions . The bioEvolutionary perspectives informed by life-history theory  have beeIt is not feasible or efficient to provide all disease prevention interventions to all people. Therefore, it is crucial to identify at-risk groups to whom clinicians can offer targeted, appropriate interventions as early as possible. A better understanding of how life-history traits relate to disease etiology and risk can help us determine whether specific individuals at high risk of certain diseases can be identified based on certain life-history patterns. Using a short life-history interview or medical chart review to identify these individuals would be clinically easy, cheaper, and simpler than screening methods that involve biomarkers or neuroimaging. The ability to identify high-risk individuals based on certain life-history patterns would open up new opportunities to intervene preemptively.evolutionary mismatch. Evolutionary mismatch occurs when an organism is exposed to an environment that exceeds its adaptive capacities, and it is one of the core pathways by which evolutionary processes can lead to ill health . Similarly, the replacement of breast milk with artificial formula is an evolutionary novelty with long-term metabolic outcomes , which encompasses the impacts of the modern socioeconomic and physical environment on the health of the population, thus shifting the focus of intervention to population- and systems-based measures .The concept of Anthropocene-related disease can be extended from the evolutionary principles of mismatch. For example, explanations for the rapid rise in the prevalence of allergic disease have generally been based on the “hygiene hypothesis” and the consequences of avoidance of parasites and allergens in early life . Other mLepus americanus) due to predator exposure has been shown to have adaptive value via heightened offspring sensitivity to stressors  . One of via cash rewards and lotteries (positive incentives), as well as by increasing the costs of non-compliance, by restricting travel or entrance into social venues for the unvaccinated (negative incentives). Negative incentives helped stimulate an immediate surge in the uptake of COVID-19 vaccines in France . Cooperation between unrelated individuals is hard to maintain. Enforcing public health measures through legislation and policing is often impracticable and costly, and can infringe on human rights. A behavioral ecological approach predicts that individual costs and benefits drive behavioral decision-making , so manin France .Reputational costs are one of the few ways to enforce cooperation between unrelated individuals . HoweverSome decisions often described as “problematic” are actually not so, and we should respect the heterogeneity in payoffs experienced by different groups within society. For example, if a young woman decides to have a baby when she is young and single, the variety of costs and benefits to her may reflect such factors as the ability of her mother to help her with childcare before the mother succumbs to any age-related health problems , and notOur goal has been to imagine a future in which evolutionary medicine accelerates biomedical solutions and informs effective public health policies. As we all face an increasingly uncertain future, the effective application of evolutionary medicine’s many tools and lenses   will be A broad range of predictions and models informed by evolutionary principles can be harnessed to support researchers working to counter the adverse health effects anticipated in the century to come. We have outlined some of the most important areas in which evolutionary approaches are being used to develop more effective strategies for a range of human health concerns. We have shown how evolutionary medicine’s profoundly integrative approach connecting health across generations, species, and ecosystems can reveal insights otherwise obscured by traditionally reductive perspectives.As the geneticist and evolutionary biologist Theodosius Dobzhansky asserted, “Nothing in biology makes sense except in the light of evolution”  and in t


Social influence is a central topic in social psychology, both as a field of research inquiry and as a fundamental process involved in a wide gamut of social psychological phenomena. Researchers and theorists in this field are interested in how people change their beliefs and attitudes by knowing that others  share a different opinion. The goal of this Research Topic is to present recent social influence research by focusing on theoretical advances, applications, and methodological issues.In two articles of the Research Topic, social influence theorizing is applied to provide solutions to the pressing social question of how to improve individuals' thinking and behavior toward climate change.Seyranian et al. employ the Context Comparison Model (CCM) to develop persuasive communication concerning global climate change. They focus on attitudes and perceptions of the plausibility of climate change. CCM is a general model of social influence that considers the importance of target's attitudes (weak or strong), source status , and issue under consideration (subjective or objective) in the process of attitude change. They found that in terms of attitudes toward climate change (subjective task), communication coming from ingroup sources, and especially ingroup minorities, were more persuasive. In terms of plausibility of climate change (objective task), outgroup sources, and especially outgroup majority, had a persuasive advantage. These findings underline the complex social psychological processes affecting individuals' evaluations and perceptions of climate change. Those developing pro-environmental communications may be well-served by taking these complexities into account.In an experimental study, Avery and Butera also applied social influence theorizing to the climate crisis and asked whether minority messages that propose radical economic and societal changes could facilitate pro-environmentalism. They examined how exposure to counternormative pro-environmental minority messages  could trigger different emotional reactions as a way of resisting the suggested change. Interestingly, they focused on the emotional reactions toward the message, a topic that has not been investigated systematically in the literature of social influence, and especially emotions with coping potential (control-oriented). A qualitative (employing semi-structured interviews) and a quantitative (employing online survey) study showed that participants reported higher control-oriented emotions (like anger and fear) than lower control-oriented emotions (like sadness). This suggests that the pro-environmental degrowth message is perceived as threatening and these emotional reactions help individuals to restore their support for the dominant paradigm of growth and thus resist change. Interestingly, this pattern of results was more pronounced among men, who are presumably socialized to maintain the status quo and preserve their status in society.Quiamzade and Lalot take a novel approach by studying the topic of dehumanization  as an influence process. They test the intriguing idea that animalistic dehumanization of a minority group (Roma beggars) could function as a social influence strategy that would immunize individuals toward subsequent favorable messages toward the minority group. Participants initially received one of three possible initial messages depicting minority groups in a manner that was negative animalized, negative humanized, or positive humanized. Then, all participants received a second message advocating for minority rights. Although both negative animalized and negative humanized conditions led to negative attitudes and discriminatory behavioral intentions toward the minority, it was only in the latter condition that these effects persisted even after exposure to favorable messages advocating for the rights of the minority group. Animalistic dehumanization of the minority group thus seems to function as an influence strategy immunizing individuals against the influence of the subsequent positive message. These findings could be useful in understanding the lasting effects of pejorative and discriminatory discourse against minority groups in our societies, even in the face of positive pro-minority advocacy.In their study, Linne et al. position their work within the paradigm of social cognition and examine the dynamic nature of information processing in persuasion. They focus particularly on the specific sequence of processing information during an attitude change attempt leading to assimilation or contrast outcomes. They propose the model of sequential information processing whereby inferences drawn from initial exposure to information may bias the processing of subsequent information. Results suggest that the sequence of the same arguments determines the emergence of assimilation or contrast outcomes depending on the processing of the valence of information. These initial results provide useful insights for persuasion by two-sided messages, with strong contrasting arguments being more persuasive when introduced after unambiguous contrary arguments.Prislin lays out a revitalizing agenda for future research in minority influence, where attention should be paid to social change itself and not only on the cognitive processes and attitudinal changes induced by minorities, which have occupied the lion's share of social influence literature to date. Prislin proposes three important conceptual and empirical points. The first is that influence unravels over time and important questions remain about constructions of influence over time, how attitudes change evolves for message recipients, and how it spreads among groups. The second concerns the dynamic nature of influence. Factions within and between groups compete to advance their positions. Gaining or losing social support due to successful or failed influence has reciprocal effects on both sources of influence. The third concerns the motives behind minority influence. Social change is pursued because minorities: (a) seek social validation, having a sense of correctness that motivates them to exert influence, (b) seek social acceptance, striving for social belonging and acceptance of their distinct identity, and (c) seek social control, endeavoring to access tangible benefits . These points provide a useful basis for advancing social influence research.Finally, The articles of this Research Topic contribute to the current social influence research by dealing with real life and diverse social phenomena , the underlying cognitive processes which foster development of a research agenda for the future, which if adopted, could not help but benefit society.AG: Writing—original draft. SP: Writing—review and editing. GP: Writing—review and editing. WC: Writing—review and editing.


Prior research has established the greater exposure of African Americans from all income groups to disadvantaged environments compared to whites, but the traditional focus in studies of neighborhood stratification obscures heterogeneity within racial/ethnic groups in residential attainment over time. Also obscured are the moderating influences of broader social changes on the life-course and the experiences of Latinos, a large and growing presence in American cities. We address these issues by examining group-based trajectory models of residential neighborhood disadvantage among white, Black, and Latino individuals in a multi-cohort longitudinal research design of over 1,000 children from Chicago as they transitioned to adulthood over the last quarter century. We find considerable temporal consistency among white individuals compared to dynamic heterogeneity among nonwhite individuals in exposure to residential disadvantage, especially Black individuals and those born in the 1980s compared to the 1990s. Racial and cohort differences are not accounted for by early-life characteristics that predict long-term attainment. Inequalities by race in trajectories of neighborhood disadvantage are thus at once more stable and more dynamic than previous research suggests, and they are modified by broader social changes. These findings offer insights on the changing pathways by which neighborhood racial inequality is produced. Two related facts have been established in the neighborhood demography of racial stratification. One, exposure to disadvantaged residential contexts is strongly associated with a host of quality-of-life indicators. Although disagreements exist on the causal status of neighborhood effects, there is little doubt about the strength or consistency of associations and there is a plausible case for the consequential effects of exposure to neighborhood disadvantage on well-being –4. SeconHowever, the traditional focus in neighborhood stratification research is on average residential attainment—the typical residential environments by which individuals are surrounded over extended periods—which we argue obscures important dynamic heterogeneity within and between racial/ethnic groups over time  ..race, coFinally, after reducing the heterogeneity in the individual-level neighborhood poverty trajectories to a set of distinct group trajectories, we perform multinomial logistic regression models to analyze how membership in the different trajectory groups varies as a function of time-invariant and baseline predictors measured prior to the start of the trajectories (Nagin 2005). For our multinomial logistic regression, we construct a categorical measure denoting the five neighborhood poverty trajectory groups (identified via GBTM) as our outcome variable. In these models, we include all time-invariant and baseline measures from GBTM as predictors (described above). Additionally, we account for whether a child was residing in a high-poverty neighborhood at baseline .All coefficients from multinomial logistic regression models are reported as log-odds. This approach allows us to simultaneously estimate both the relationship between baseline time-invariant covariates with the probability of trajectory group membership and the parameters of the trajectories themselves . This enSimilar to other longitudinal modeling techniques, group-based trajectory models retain respondents even if they are missing from some waves, so missing data at a given age should not affect trajectory development ,63—i.e.,On the other hand, missing covariate data that is not random may introduce bias in multinomial regression models that analyze the association of these risk factors with the identified trajectory groups. For our analysis, we eliminated sample members that had missing data on the baseline family characteristics included in our models. This restriction reduced the full geocoded sample (N = 1057) to 838 sample members. Appendix Table S2 in younger (0-year-old [birth] cohort) and older (9/12/15-year-old) cohorts. As expected, we observe differences in mean neighborhood poverty race between white, Black, and Hispanic children at baseline that continues over the course of the study period. We also observe differences within racial/ethnic groups between cohorts. The disparity in exposure to neighborhood poverty rate between cohorts widens beginning in the mid-1990s and continues until around 2008, coinciding with the period of the Great Recession and its aftermath. After 2010, the period cohort trend lines for white and Hispanic individuals converge, while they begin widening again for Black individuals.We begin by descriptively analyzing trends in neighborhood sociodemographic contexts among sample members by race and period cohort from 1995, the baseline of the PHDCN, to 2018. Does childhood neighborhood context follow people from childhood through young adulthood? Our unadjusted descriptive analyses provide suggestive evidence of meaningful relationships between race and cohort on children’s exposure to neighborhood poverty in each year and over time. Black and Hispanic sample members seem to experience more heterogeneity in their trajectories of neighborhood exposure to poverty.Our next set of analyses relies on group-based trajectory models (GBTM) to identify potential latent subgroups experiencing similar trajectories of exposure to residential contexts during the early life course. It could be the case that there are other unifying characteristics aside from race and cohort that group sample members into similar trajectory classes.trajplot command in Stata (version 16). To illustrate findings, we generated figures that display the trajectory subgroups identified in our GBT models using the durably advantaged (DA) trajectory (27.6 percent), experience effectively zero risk of residing in a neighborhood with greater than 20 percent poverty as they age through their 20s. Conversely, the persistent poverty (PP) trajectory is characterized by increasing propensity of exposure to high-poverty neighborhoods in late childhood followed by continuous, severely elevated propensity of residence in high-poverty neighborhoods. Three trajectories are characterized by changing propensity of high-poverty neighborhood exposure over the life course. For children in the increasing poverty (IP) trajectory, the low propensity of residing in high-poverty contexts increases sharply from adolescence to adulthood. On the other hand, those in decreasing poverty (DP) trajectories experience the opposite trend as their substantially elevated risk of high-poverty neighborhood exposure decreases dramatically beginning in adolescence. The probability of exposure fluctuates moderately during late childhood and early adulthood for individuals in the marginal poverty (MP) trajectory, though the probability remains lower at nearly all ages compared to the IP and DP trajectories.We identified five poverty trajectories. Two poverty trajectories are characterized by stability while three feature changing exposure to neighborhood high-poverty contexts at different stages of the early life course. Children in the largest group, the To alleviate concerns that our group-based prevalence models were sensitive to our threshold definition for high-poverty neighborhoods (>.20), we also plotted the actual neighborhood poverty rate for each of the classes identified via GBTM . Hispanic sample members are even more clustered in the group experiencing decreasing poverty exposure (DP). The changing fortunes of Hispanic sample members could be the result of intergenerational differences within families as they migrate into lower-poverty contexts after leaving their childhood and adolescent neighborhoods. It could also indicate important differences from unobserved macrolevel influences between Hispanic respondents that experienced the transition to adulthood during different periods. Finally, it could also be the case that higher-SES residents are moving into Hispanic sample members’ existing neighborhoods, thus changing the poverty contexts while sample members age in place. Gentrification is an example of this type of residential sorting process, and this explanation is consistent with prior research on gentrification of Chicago’s Hispanic neighborhoods since the 1990s (Hwang and Sampson 2014). This is also consistent with earlier descriptive findings  which prThe striking imbalance in white sample members’ representation in the trajectory groups  underscores white children’s seemingly intractable advantage–their privileged starting point generally follows them through the early life course.Summarizing our key findings, Black children have the highest amount of within-race variation. Hispanic children have some variation but differ from Black and white children in that they are far more likely to be in the “middle” trajectory. White children have little internal variation and are overwhelmingly durably advantaged with respect to their residential environments. Children coming of age more recently (younger cohort) tend to experience more advantaged neighborhood trajectories relative to those born earlier (older cohort).Finally, we further explore descriptive characteristics of trajectory groups, but from a multivariate framework. The relative likelihood of following any non-DA trajectory compared with following the durably advantaged trajectory is substantially higher for Black individuals relative to whites (reference category), as indicated by the significant negative main effects across all trajectories. Hispanic children are also more likely to follow a non-DA trajectory relative to white children, though the relative risk is substantially lower compared to Black children, and the likelihood of membership is fairly similar for all non-DA groups. While Black sample members, compared to whites, are associated with a higher risk of membership in all high-poverty trajectory types relative to those in durably advantaged low-poverty trajectories, the odds of following the persistently high-poverty neighborhood trajectory are substantially and significantly greater. Put together, and mirroring the descriptive results from Parental employment in childhood significantly lowers the risk of membership in the PP and MP trajectories, relative to membership in the DA trajectory. On the other hand, having a parent that attained a college degree attenuates the risk for membership all non-DA groups. Childhood family income does not significantly predict membership in any of the trajectories, demonstrating that not all baseline family SES factors lower the risk of membership in non-DA groups, relative to the DA group. However, in models that separately interact race with cohort and family income, the risk of following the IP, MP, and DP (trend level significance) trajectories, relative to following the durably advantaged trajectory, is significantly lowered for Black children from high-earning childhood households  or marginal poverty (MP) trajectories is significantly lower for the younger birth cohort relative to the older cohort across similar ages, and slightly and marginally lower for following decreasing poverty trajectories. This underscores, on a conceptual and empirical level, the importance of disaggregating between children growing up during different periods since specific macrolevel historical context may shape their trajectories differently depending on when they came of age ,40.Our trajectory analyses uncover both stability and change in exposure to neighborhood poverty by race and birth cohort. Advancing beyond prior neighborhood-focused research that typically evaluates an average neighborhood context, our study provides a nuanced portrait of individuals’ cumulative residential environments that incorporates the sequence and timing of exposure. Over time, and between children coming of age during different periods, we find strikingly stable homogeneity of white advantage and dynamic heterogeneity of nonwhite disadvantage in their residential environments. An important finding from our study is that heterogeneity in neighborhood poverty impacts Black children the most, and, to a somewhat lesser degree, Hispanic children. Our results imply that researchers and practitioners should dig deeper into the correlates and explanations for the differences within Black and Hispanic children. Our group-based trajectory method allows us to conclude that typical methodological approaches that capture of an average effect, such as growth curve models or transition matrices, miss this important distinction of within-group heterogeneity.Our study first examined the different neighborhood poverty trajectories that individuals follow as they age from childhood to young adulthood and asked whether they vary within and between racial/ethnic groups. Does childhood neighborhood context follow individuals as they age through different life stages? For white children, our results suggest that it does. Findings from our group-based trajectory analyses further reveal that most white children travel along the same advantaged path regardless of when they came of age.These findings arguably demonstrate another way in which white advantage persists in contemporary society. While there are differences in their absolute levels of exposure to neighborhood sociodemographic contexts, white sample members from both cohorts, younger and older, overwhelmingly follow durably low-poverty residential pathways that continue through adulthood, regardless of baseline family factors during childhood. Thus, while prior work examining differences in neighborhood contexts often observes from the perspective of nonwhite children’s disadvantaged residential contexts, our results suggest that another useful frame for understanding longstanding disparities in residential environments is through a lens that focuses on the persistence and resiliency of white advantage.On the other hand, Black and Hispanic trajectories are characterized by considerable heterogeneity. Both within and between racial/ethnic groups, Black and Hispanic children follow multiple residential pathways. Interestingly, Hispanics are overrepresented in the residential trajectory with a relatively lower risk of poverty than all groups except for the durably advantaged trajectory. Hispanics from the younger cohort tend to follow lower-poverty trajectories than older Hispanics, offering some evidence of period effects.decreasing risk of poverty exposure. Moreover, both Black and Hispanic sample members are represented in all trajectory groups. These collective results suggest important differentiation in the residential experiences of nonwhite children over the life course that past work has overlooked. Our findings call for future work to view the residential pathways of nonwhite children as more nuanced or heterogeneous than prior research acknowledges, beyond the persistent poverty pathways that confirm durable racial inequality compared to white individuals.While Black sample members are overrepresented in the residential trajectory characterized by increasing propensity of residing in high-poverty neighborhoods from childhood to adulthood, they are also overrepresented in the trajectory that experiences Our study further explored potential cohort differentiation in residential trajectories of exposure to neighborhood disadvantage. By incorporating an inter-cohort analysis, our study foregrounds how macrolevel forces differentially influence residential poverty trajectories of children that grew up and came of age during different periods, a form of cohort differentiation due to social change. Our results indicate differences in the risk of neighborhood poverty exposure between cohorts, with the younger birth cohort generally experiencing the most advantaged residential pathways. Identifying empirically the precise social changes that account for cohort differentials in trajectories is beyond the scope of this paper, but they deserve attention in future research. For example, did the Great Recession and its ensuing foreclosure crisis, which coincided with early adulthood for the older cohort, result in an economic fallout that was worse and more enduring for older cohort members relative to the younger cohort members who were experiencing early adolescence during this same period? Did the deconcentration of poverty in Chicago neighborhoods since the 2000s result in younger cohort members generally being more exposed to lower poverty neighborhoods overall? Can the dynamic residential trajectories for Hispanic and Black children be explained by more widespread gentrification in Chicago neighborhoods since the mid-2000s? In the case of gentrification, an individual’s exposure to neighborhood poverty could change as the result of higher-SES households moving into their existing neighborhoods or nonwhite gentrification that sees Black and Hispanic households moving to gentrifying neighborhoods. Although these are important questions, by conditioning our analyses on classic background factors of childhood exposure, we can nonetheless reasonably conclude that broader social changes rather than cohort compositional features are the main driver of differences in poverty trajectory groups across younger versus older cohorts.Our study leaves open several other questions as well, which we hope will motivate future work. Our study focuses on individuals’ varied sequence of exposure to one economic dimension of residential context: neighborhood poverty. Future research should examine the various pathways of exposure that children follow in terms of other sociodemographic and ecological features, such as racial isolation or environmental toxins like lead or airborne pollution. Future research could also use the identified neighborhood trajectories as predictors and examine the effects of following various residential pathways on later-life outcomes . AnotherIn sum, that we find both durability (of white advantage) and dynamism (in nonwhite pathways) suggests the need to change the way we frame residential processes of stratification over time. That we find differences between cohorts, controlling for their baseline composition, suggests that we pay greater attention to the ways in which individual pathways intersect with broader population dynamics and macrolevel change, a classic theme of demography and yet one which is often unrealized in longitudinal studies of neighborhood stratification. While much past work highlights overall disparities between racial/ethnic groups in their exposure to neighborhood environments, our findings highlight the theoretical and empirical need to also consider the dynamic heterogeneity that exists within racial/ethnic groups and between periods.S1 Appendix(DOCX)Click here for additional data file.


Electroconvulsive therapy (ECT) is one of the most controversial treatments in medicine, mainly because of its still unknown mechanism of action and uncertainty about cognitive side effects. ECT is used mainly when antidepressant medications do not result in an adequate response in severe depression, and may also be indicated for other disorders. During the acute phase after electroconvulsive therapy there are better cognitive outcomes with unilateral ECT compared to bilateral ECT.This literature review aims to analyze the validity of electroconvulsive therapy despite the cognitive impairment and effectiveness of electroconvulsive therapy.The method used was a literary review based on articles published in Scielo and Pubmed. Eighteen electronic articles in English were used in a 10-year time frame, using the term electroconvulsive therapy as descriptors in the title, as well as cognitive impairment in all fields.We observed that older individuals benefit the most from ECT, with faster response rates and higher remission rates in rapid responders, on the other hand they have a higher risk of cognitive side effects induced by electroconvulsive therapy. Anterograde and retrograde amnesia usually resolve within months. Recovery from retrograde amnesia may be incomplete, resulting in permanent amnesia for events that occurred close to the time of ECT. Right-sided or bilateral electroconvulsive therapy was more effective in treating depression than left-sided. Patients who used right unilateral electroconvulsive therapy had less impairment of verbal memory and post-ictal recovery and faster reorientation compared to left unilateral and bilateral, whereas left unilateral ECT showed a smaller decline in visual memory and non-verbal tests. Bilateral ECT is more effective and faster acting, but is associated with more cognitive impairments compared to unilateral ECT.We can conclude that ECT is an effective, safe and tolerable treatment, which results in faster and higher remission rates compared to treatment alone with pharmacotherapy. Cognitive effects are largely transient, usually ending within three months. The decision to use unilateral right, left, or bilateral ECT should be made individually for the patient and should be based on a careful assessment of the relative priorities of efficacy versus minimizing cognitive impairment.None Declared


Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of the pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants and potential interactions among determinants of perinatal depression across four domains  and appraise the quality of methods applied.Four databases  were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, the evaluation of depression was specific to a discrete facet of the perinatal period with probable psychological consequences , or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias.Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 28% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged when determinants across domains were aggregated. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias.Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression. The leading underlying cause of perinatal death is mental health conditions . DepressThe heterogeneous nature of depression symptoms coupled with the stark overlap of “normal” pregnancy symptoms make early detection and intervention difficult. Therefore, the prevalence of perinatal depression is likely underrepresented in part due to the lack of diagnostic expertise in the clinicians who are most likely to interact with at-risk individuals, high variability in existing screening practices, and underreporting of symptoms due to perceived stigma –11. StilA majority of research on the etiology of perinatal depression has attempted to dissect it into two broad camps  . InvestiSince perinatal depression is considered to have a multifactorial etiology, siloed approaches to investigation may inadvertently omit significant findings related to interactions among factors from differing domains that can advance our understanding of risk and onset. In an era of team science, integrative approaches to investigation are not only feasible but desirable to address some of the world’s most complex health problems, like perinatal depression. This review aggregates existing literature across various scientific domains and uncovers novel interactions that warrant further investigations into the etiology and risk for this complex condition. Advancements in knowledge of distinct determinants and interactions will not only improve our ability to detect existing symptoms but will also progress our aptitude for determining risk status and implementing risk mitigation strategies . TherefoThe literature search took place in December 2022. The following databases were searched for articles that encompassed all or some of the specified determinants: PubMed, CINAHL, APA PsycInfo, and Web of Science. The following search terms were used across all databases in the Title/Abstract field:  AND  AND (determinants or characteristics or factors) AND (tryptophan or serotonin or kynurenine or immunology or immune response or immune system or inflammation or inflammatory response or cytokines) AND (metabolites or metabolomics or metabolism) AND .The study selection process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) methodology . Search Articles from any date were included if they focused on a timeframe within the perinatal period , had participants that were 18 years or older, were available in the English language, investigated factors that belonged to at least one of the four domains , and had an outcome of depression or depression symptoms. We define the four domains as follows: 1) biological: individual features unique to a person that have a biological basis  2) behavioral: either a conscious or unconscious action or inaction in response to internal or external stimuli  3) environmental: physical surroundings or conditions a person lives or functions within  4) social: one’s experiences with relationships or interactions with others  , 29Articles were excluded if they were non-peer-reviewed publications, review/meta-analyses, and commentaries. Further, articles were excluded if outcomes were not specific to pregnant/postpartum individuals , determinants investigated were not related to depression or depression symptoms , and the outcome or evaluation of depression or depression symptoms were specific to a discrete facet of the perinatal period with implied potential for psychological consequences .After all articles were compiled and duplicates were removed, six authors  independently screened the titles and abstracts to determine which articles met inclusion criteria. All articles were then subsequently cross-checked by the primary author to make a final determination on inclusion. Of the articles that remained after the title and abstract screening, five authors  independently completed a full-text review. Any concerns related to inclusion during any of the screening processes were resolved by discussion among the primary author and the respective co-author.Quality appraisal screening was independently conducted by two authors  to ascertain any methodological or risk of bias concerns. Since quality appraisal assessments can be subjective in nature, we selected two commonly used quality appraisal tools , respective to study design, to guide and standardize the process , 31. TheThe following data were extracted from the included articles: country, purpose or aims, study design, recruitment and sampling method, perinatal period investigated, number of time points, sample description, what determinants were investigated, methods for measuring determinants and depression, method of analysis, and findings related to the relationship among determinants and depression or depression symptoms. Once data extraction was complete, the data were organized by descending date respective to the time-period investigated  and then synthesized.The PRISMA flow diagram provides an overview of the search results Of the 25 articles included in the final review, 80% of the articles were published in 2011 or later –49. Thoua prior power analysis to calculate the needed sample size with half of those being US based studies  to methionine [met] is suggested to reduce the activity of the COMT enzyme that metabolizes the aforesaid neurotransmitters [COMT variant is minimally explored in perinatal depression, Comasco and colleagues (2011) found an association among the polymorphism  and PPD symptoms at 6 weeks but not at 6 months. Additionally, genetic variation in the Monoamine oxidase A (MAOA) gene is suggested to contribute to depression, specifically when MAOA activity is high. Higher gene activity occurs when there is a polymorphism in rs1137070 where a C allele replaces a T. Higher MAOA activity induced by this polymorphism may result in rapid catalyzation of the neurotransmitters serotonin and norepinephrine [COMT-MAOA interactions to be significantly associated with PPD symptoms. For instance, among low MAOA carriers , the Met variant of the COMT gene was related to PPD symptoms; whereas the high MAOA variant  was related to PPD symptoms only when combined with the Met allele of COMT. In terms of gene-environment interactions, COMT-Val158Met was also associated with PPD symptoms when psychiatric history and stress were present. This interaction effect may explain why studies have reported significant associations of both MAOA polymorphisms with depression.Catechol-O-methyltransferase (smitters –84. Thisnephrine . Howevernephrine . With reTPH2), the rate limiting enzyme of serotonin biosynthesis, in those with perinatal depression [TPH2 gene plays a major role in the regulation of the neurotransmitter serotonin, and genetic variants of TPH2 are suggested to play a significant role in both susceptibility to depression and response to a commonly prescribed treatment, selective serotonin reuptake inhibitors (SSRIs) [TPH2 C2755A polymorphism occurred only in those with perinatal depression and/or an anxiety disorder. Further, though significance faded after Bonferroni correction, a risk analysis demonstrated that the TPH2 C2755A polymorphism increased risk of perinatal depression and exhibited a dominant gene effect. However, it is important to note the reported study is specific to a Han Chinese population, and the authors position this polymorphism as a potential population specific indictor of depression risk based these findings and current evidence in Han Chinese populations. Also exploring TPH2 polymorphisms, Fasching and colleagues (2012) found the single-nucleotide polymorphism (SNP) in intron 8 (rs10879354) to be the only SNP to show consistent effects across all time points  in a German population. Since TPH2 polymorphisms influence the activity of neurotransmitters commonly associated with depression in non-perinatal and perinatal populations [Two studies explored polymorphisms of tryptophan hydroxylase 2  , 88. Linon 8 rs109354 to bA negative association among vitamin B12, cobalamine deficiency (cB12), and serotonin were observed with probable PPD . AdequatOther micronutrient alterations that were associated with prenatal depression were total n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). EPA and DHA are two notably important fatty acids given they are critical for the development and function of the central nervous system in both perinatal persons and the developing fetus and have anti-inflammatory properties . Chang aBrain serotonin-1A (5HT1A) receptor binding potential, as measured by positron emission tomography (PET), suggested a 20–28% reduction in postsynaptic 5HT1A receptor binding in those experiencing PPD . The mosSix studies , 46, 55 Though specific to the third quartile (ascending quartiles per glycemic index/load), Murakami and colleagues (2008) found higher dietary glycemic index (GI) decreased the risk of PPD, while no associations were found between PPD and dietary glycemic load (GL). Lower milk, meat, and egg consumption during the postpartum period was associated with probable PPD . FurtherTwo studies independently demonstrated alcohol consumption  during pA total of seven studies , 51, 53 Two commonly suggested risk factors of perinatal depression, psychiatric history  and signConsistent with current evidence, perceived stress was positively correlated with perinatal depression , 40, 51.One study  found foThe specific factors explored across the four domains were highly variable. Therefore, this review does not claim to present an exhaustive description of all potential interactions that can be interpreted from findings of the aggregated factors. Due to patterns in which interactions with TRP and its metabolites emerged, we specifically chose to focus on these interactions as they may suggest a potential role in perinatal depression risk and onset.Although minimally explored in perinatal populations, disruption in serotonin or the serotonergic system is widely considered to contribute to depression onset, maintenance, and response to treatment  in non-perinatal populations , 98, 99.The mechanisms underlying the increased uptake of TRP in the brain are not fully understood, but some evidence suggests higher dietary carbohydrate intake can promote the uptake of TRP in the brain resulting in increased serotonin , 101. InThough the life-stage itself induces a unique immune and inflammatory response, additional factors throughout the perinatal period, such as the social, environmental, and behavioral factors discussed in this review  may further promote immune and inflammatory responses and increased TRP degradation down the KYN pathway predisposing one to depression onset. Further, sleep disturbances are common perinatally and are often attributed to “normal” pregnancy and postpartum symptoms, but sleep disturbances also happen to be a common symptom of depression and/or anxiety in non-perinatal populations. Though sleep disturbances are linked to the TRP and KYN pathways, they are not considered in any study in this review yet may serve as a moderating factor that perpetuates a negative feedback loop which contributes to chronicity or a risk for symptom relapse, notably in the postpartum period due to poor quality of sleep as a result of child rearing responsibilities. Meaning, certain biochemical pathways may account for specific depression symptoms and indicate subtypes of perinatal depression that can be leveraged to increase precision in detection and intervention.In the context of PPD, these findings may indicate when dietary intake of tryptophan or tryptophan uptake promoting foods are limited amid immune and inflammatory responses, competitor amino acids are being prioritized for transport across the BBB and/or TRP may be shunted towards the KYN pathway. Moreover, both pathways may result in decreased production of the neurotransmitter serotonin and explain the risk for and onset of PPD, and the level of risk would be further increased for those with a genetic predisposition  or those experiencing the other biopsychosocial or behavioral factors discussed in this review. Thus, future investigations are needed to further explore these prospective interactions as these interactions may serve as significant risk factors of PPD that can be detected and intervened upon during pregnancy.The factors discussed in this review have been independently indicated as probable determinants of PPD risk and onset. However, what is not evident in independent investigations but is demonstrated in this review is that various interactions among diverse determinants and TRP metabolism may provide a deeper understanding of what contributes to the pathophysiology of perinatal depression or perinatal depression risk. Future investigations are needed to address methodological issues in maternal mental health science and care as well as explore these prospective interactions as these interactions hold potential to evolve as a PPD risk phenotype (observable characteristics). Such a phenotype can serve as a robust foundation for the development of clinically efficient yet meaningful mechanisms for risk detection and inform patient centered risk mitigation strategies. Further, the present review establishes the value of integrative approaches in the investigation of perinatal depression and suggests the application of team science principles  may be particularly useful to this area of inquiry to expedite the discovery of clinically relevant findings and strengthen scientific methods.


The brain enables adaptive behavior via the dynamic coordination of diverse neuronal signals across spatial and temporal scales: from fast action potential patterns in microcircuits to slower patterns of distributed activity in brain-wide networks. Understanding principles of multiscale dynamics requires simultaneous monitoring of signals in multiple, distributed network nodes. Combining optical and electrical recordings of brain activity is promising for collecting data across multiple scales and can reveal aspects of coordinated dynamics invisible to standard, single-modality approaches. We review recent progress in combining opto- and electrophysiology, focusing on mouse studies that shed new light on the function of single neurons by embedding their activity in the context of brain-wide activity patterns. Optical and electrical readouts can be tailored to desired scales to tackle specific questions. For example, fast dynamics in single cells or local populations recorded with multi-electrode arrays can be related to simultaneously acquired optical signals that report activity in specified subpopulations of neurons, in non-neuronal cells, or in neuromodulatory pathways. Conversely, two-photon imaging can be used to densely monitor activity in local circuits while sampling electrical activity in distant brain areas at the same time. The refinement of combined approaches will continue to reveal previously inaccessible and under-appreciated aspects of coordinated brain activity. They are composed of a profusion of diverse cells that are organized with exquisite precision to transform, store, and communicate information using a rich repertoire of signals. This complexity is perhaps nowhere more evident than in the brain, with nearly as many neurons in each human brain as there are stars in the Milky Way galaxy  that make them more conducive to combination with optical methods, also considering the challenges to keep in mind when planning a new multimodal experiment. We then outline recent studies, from the mouse brain, that have leveraged the combination of electrical and optical recording of brain activity to reveal new principles of brain function. Finally, we discuss how multimodal data can be analyzed to provide new insights and emphasize the need for new analysis and modeling approaches that permit multiscale analysis of brain data.22.1All measurement techniques have trade-offs and relative strengths and weaknesses. These factors depend on the features of the measurement apparatus, such as its spatial and temporal resolution, the accessible coverage [field-of-view (FOV) for imaging methods], and the maximum tissue depth reachable by the respective technology. However, the limitations of a given measurement also depend on the spatial and temporal characteristics of the specific physiological activity measured, as well as on how the activity is transduced into a measurable signal. Both electrical and optical techniques can assess signals across a broad range of temporal and spatial scales depending on their precise technological implementation and application  so the activity of non-spiking or electrically silent cells cannot be monitored. Likewise, it is difficult to monitor neuromodulatory activity, although electrochemical methods such as fast cyclic voltammetry provide some access using specialized electrodes.2.3,,In parallel to the advancements in electrophysiology, the past decades have seen rapid improvements and increased application of optical methods to monitor and manipulate brain activity. Optical recordings have several distinct advantages to electrical recordings. First, they can measure a wide range of physiological signals depending on the specific contrast agent. Optical methods can leverage intrinsic contrasts, for example, the wavelength-dependent absorption or reflectance of hemoglobin to assess hemodynamics and autofluorescence, or secondharmonic or third-harmonic generation to image anatomical features.–,,,,–,in-situ sequencing analysis of physiologically characterized cells, providing an additional dimension and degree of specificity.–Optical techniques can be broadly divided based on whether they form an image of the sampled tissue or not. Non-image-forming techniques, such as photometry, record the bulk fluorescence signal by exciting and capturing light emission through a single optical fiber, producing a single time series . The ins–,,,–Most image-forming techniques are limited to the surface of the brain due to scattering and absorption of light in tissue. Even two-photon microscopy barely reaches 1-mm imaging depth2.4We have highlighted the unique strengths and limitations of the diverse electrical and optical recording methods commonly used in systems neuroscience. We believe that the distinct strengths and challenges of electrical and optical recording modalities complement each other see . Before Box 1. Key open questions•How do idiosyncratic local neurons give rise to coherent patterns of activity?•How do single neurons integrate diverse inputs arising from distributed presynaptic partners?•What information do individual neurons contribute to brain-wide activity patterns?•How are distributed neurons organized into large-scale brain-wide states?•Do computations and transformations take place in local circuits, or do large-scale distributed networks perform computations?•How are brain-wide states dynamically regulated and what determines the transition between states?2.5,–,––,,,,–,,,Pioneering multimodal experiments, many of them combining electrophysiological and optical measurements, have already contributed significantly to our understanding of brain function. They have been especially useful in addressing two fundamental questions: (1) How is the brain’s ongoing, intrinsic activity organized and how does it affect neuronal responses? (2) How does neuronal activity relate to hemodynamics via neurovascular coupling? In a series of seminal experiments, Grinvald, Arieli, and colleagues–In addition to these two areas, simultaneous electrical and optical measurements promise to contribute to our understanding of a wide range of urgent neuroscience questions. Recent work has begun to use combined measurements to reveal how the activity of single neurons is coordinated with brain-wide activity patterns, how brain activity is organized across spatial and temporal scales, and how inputs are transformed in local circuits and transmitted to distributed partner regions to enable coordinated whole-brain states.3,,The combination of electrical and optical recording techniques in the same preparation requires careful consideration so the necessary apparati do not interfere with each other. Current and emerging advances in multi-electrode technology that render electrode arrays more conducive to the combination with optical methods make it a particularly exciting time to attempt multimodal investigations. New innovations in the fabrication of electrode arrays have improved the density of recording contacts, as well as introduced highly flexible arrays that match the mechanical characteristics of biological tissues or have substrates or electrode sites fabricated from transparent materials . Each ofBox 2. Key challenges•Geometric concerns of simultaneous MEA placement and high-NA water-dipping objective. •Potential light artifact depending on the MEA materials .•Attention must be paid to the different spatial and temporal resolutions of electrically and optically recorded brain signals when performing multimodal analysis.•There is a lack of practical and conceptual methods to mechanistically link diverse signals that reflect different levels of organization.,,,–,,Because of these limitations of conventional MEAs, multi-electrode arrays fabricated on non-silicon substrates are highly desirable for combined electrical-optical measurements. New flexible arrays have been fabricated using microelectromechanical systems fabrication techniques,,,,The advantages of flexible arrays are accompanied by some challenges. First, the density of contacts achievable on flexible MEAs is in general lower compared with similarly sized silicon arrays. This is because the size of features that can be reliably achieved when structuring conductive material on flexible substrates is in general larger than those achievable on silicon. Likewise, multiplexing has been increasingly used to increase the density of silicon arrays and can also be implemented on flexible MEAs.4The diversity of recording techniques provides flexibility to determine which combinations are ideal for a specific experimental question. Of primary concern are the required spatial and temporal resolution, the signals of interest, the target brain areas, and the desired coverage. Recording electrically and optically from the same population of cells can provide complementary information about local neural circuit activity. On the other hand, recording from different brain locations opens the possibility to monitor the activity of multiple distributed populations and track the transformation and routing of signals across distributed brain networks. Given the range of electrical and optical recording approaches, there are many possible combinations. To simplify, we will focus on four main configurations that have been applied recently and illustrate the power of multimodal experiments to capture brain dynamics across scales. We will highlight recent state-of-the-art applications that address the contribution of single neurons, or classes of neurons, to local and distributed population dynamics in the healthy mouse brain and discuss how they inform and enhance our understanding of brain dynamics.4.1–,In the first combination, an optical fiber can be coupled to an electrode or MEA (often referred to as an “optrode”),For example, Patel et al.4.2,–A second possibility combines electrical recordings using a penetrating MEA in a region of interest with simultaneous monitoring of large-scale activity across the dorsal cortex using widefield fluorescence imaging . Mesosco,,For example, linear silicon arrays have been implanted at an angle permitting imaging, while passing through cortex and thalamus,,,,,Widefield imaging can also be performed through chronically implanted transparent ECoG arrays4.3in vivo imaging, providing sub-micrometer resolution and allowing measurement of fluorescent indicators up to 1 mm deep in brain tissue.,On a finer level, one can combine electrophysiology with MEAs with cellular imaging, using, for example, two-photon microscopy or portable miniscopes. Two-photon imaging is the current gold-standard for cellular or subcellular ,,,,,–,Optical recordings of single-cell calcium dynamics can, for example, be related to known electrophysiological markers of population activity, such as sharp-wave ripples (SWRs) in the hippocampus.,,,Typically, the combination of two-photon imaging with electrical recordings is challenging because of the difficult geometric arrangement of objectives with short working distance and rigid electrodes, as well as the light-induced electric artifact.,,These advancements of flexible electrodes are paralleled by improvements of two-photon microscopes to record from large populations of neurons across multiple areas4.4–Lastly, it is possible to position a planar MEA below the GRIN lens of a head-mounted miniature widefield microscope to record population synchrony in addition to dense, unbiased imaging of cellular activity . Like th5We have illustrated the power of combined electrical and optical recordings for the study of brain function and highlighted recent work demonstrating its potential. We believe that it is a particularly fruitful time to perform multimodal and multiscale studies because of the remarkable recent advances in electrode and imaging technologies, as well as molecular probes. We look forward to the new perspectives that future studies will provide on large-scale brain dynamics and the integration of cellular signals into whole-brain activity patterns in the awake, behaving animal see Box .,,,,,–Neuroscience has classically treated neurons as individual units of computation in the brain and sought to understand the brain through the isolated activity of single neurons, local populations, or brain areas. By recording the activity of single neurons while manipulating sensory, motor, or cognitive variables, it has been possible to characterize tuning properties or transfer functions that relate these external variables to the activity of single cells . This ap,,,,,,de novo to evaluate their effects on isolated cells or populations? Given the varied specific and pronounced behaviors that can be evoked when stimulating small groups of cells, for example, in the hypothalamus,–While technical advances are making multimodal studies more practical, the data collected from multimodal studies also pose considerable hurdles in their analysis. Most analysis tools are focused on signals of a single spatial or temporal resolution, and, to date, most multiscale studies have been correlational. The analysis approach commonly employed by multimodal studies has been to either look at time-locked averages around events detected with one modality or to use a signal from one level of organization to predict a different signal at a higher or lower level of organization.


Tourniquet use is common practice in many millions of orthopaedic procedures annually. Recent reviews of risks and benefits of surgical tourniquet use have primarily involved meta-analyses, many of which have forgone a comprehensive risk-benefit analysis to simply question whether “tourniquet or no tourniquet” use produces improved patient outcomes, often leading to limited, inconclusive, or conflicting results. To investigate further, a pilot survey was undertaken to determine current practices, opinions, and understandings among orthopaedic surgeons in Canada regarding use of surgical tourniquets in total knee arthroplasties (TKAs). Results of the pilot survey showed a wide range of understanding and practice associated with tourniquet use in TKAs, especially regarding tourniquet pressures and tourniquet times, two key factors known from basic research and clinical studies to impact the safety and efficacy of tourniquet use. The wide variation of use indicated by the survey results reveals important implications for surgeons, researchers, educators, and biomedical engineers, to better understand the association between key tourniquet parameters and outcomes assessed in research, which may be factors leading to their often limited, inconclusive, and conflicting results. Lastly, we provide an overview of the overly simplified assessments of tourniquet use in meta-analyses, whose conclusions may not provide an understanding of how or whether key tourniquet parameters might be optimized to retain the benefits of tourniquet use while mitigating the associated real or perceived risks. Modern pneumatic surgical tourniquets consist of a microprocessor controlled pneumatic tourniquet device first invented by McEwen in 1981 to improve tourniquet safety and performance . Basic rIn recent years reviews of the risks and benefits of surgical tourniquets have primarily involved meta-analyses, many of which have simplified the risk-benefit analysis to ask the question of whether “tourniquet or no tourniquet” use produces improved patient outcomes, often leading to limited, inconclusive, or conflicting results –22. MetaTourniquet use is common practice in several million orthopaedic procedures annually in North America, thus, the ongoing pursuit of optimal tourniquet use cannot be overstated. A cross-disciplinary understanding of the impact and importance of key tourniquet parameters is essential to improve patient outcomes by incorporating the results of basic research and published clinical studies into biomedical engineering advances, with widespread learning and adoption of updated tourniquet technology and use practice. While the capabilities of surgical tourniquet technology have continued to evolve to improve their safety and utility, the lack of association between key tourniquet parameters and outcomes assessed in recent meta-analyses –22 demonOver the past two decades, multiple surveys have been administered in different regions and specialties assessing tourniquet practices –25. ResuThe survey results and resulting discussion are intended to serve as a stepping stone for future research, thereby allowing the oversimplified “tourniquet or no tourniquet” question posed by limited or inconclusive meta-analyses to be advanced to the understanding of how or whether key tourniquet parameters might be optimized to retain the benefits of tourniquet use while mitigating the associated risks and improving patient outcomes.via email by CAS. The email included an online survey link and the outlined objectives of our study. The survey was administered through Microsoft Forms. The survey period was six weeks (October 2021–November 2021) and additional two follow-up emails were sent to complete the survey. The survey was anonymous and voluntary.The survey was distributed to all 161 staff orthopedic surgeon members of the CAS. After review and approval by the CAS research committee the survey was distributed The survey consisted of 59 total questions that ranged from demographics to specifics on tourniquet use. The survey utilized skip logic branching to deliver the questions, as identified in the The results of our pilot surgical practice survey involving 91 orthopaedic surgeons (56.5% response rate) have important implications. These results are summarized in Per the survey's skip logic branching, the sixty-five percent of respondents who indicated they currently use tourniquets completed the remaining sections of the survey. The top reason for tourniquet use was improved visualization/bloodless field (88%), followed by performing cemented TKAs, consistency with training, and faster operative times. The most frequent adverse events reported were bruising/pinching under the tourniquet and short-term pain, which majority believed were related to improper tourniquet use , yet only 8% reported use of contoured tourniquets to better fit contoured limbs and 32% reported that they did not use limb protection beneath cuffs to minimize soft tissue injuries.Despite substantial evidence in basic and clinical literature that patient safety and probability of harm are affected by both the duration of applied tourniquet pressurization (“tourniquet time”) and the level and gradient of applied tourniquet pressure (“tourniquet pressure”), only 83% and 72% of tourniquet users reported believing that reducing tourniquet times and pressures respectively reduces the probability of harm. Furthermore, 62% reported always using fixed pressures and 37% reported that they would modify tourniquet pressure settings based on patient parameters, most often based on systolic blood pressure and limb size, and no surgeon reported use of measuring limb occlusion pressure (LOP) to personalize the tourniquet pressure. Almost all respondents who currently use tourniquets (88%) were interested in new evidence-based guidelines regarding these parameters, a significant implication for this investigation. •The specific levels of pneumatic pressure were used, and why; •The specific duration of tourniquet pressurization; •The inflated tourniquet time relative to the overall procedure time; •The specific type of tourniquet cuff used for each patient, and the corresponding fit of the selected cuff to the patient's limb; and •The specific tourniquet instrument used .The majority of tourniquet focused original research articles published over the past few decades do not report on the key tourniquet parameters described above. Some publications will describe the dimensions of tourniquet cuff used, and the standard protocol for setting tourniquet pressure. However, unless the research article is investigating the direct impact of a specific tourniquet parameter on the measured outcome , 13.3 kPa (100 mmHg), and 0.8 bar (600 mmHg) . Mean toFrom a cross-disciplinary perspective, recent advances in biomedical engineering have led to advances in technology which can be adapted to the needs of individual patients, surgeons and procedures. One key advancement in technology is the ability to personalize the tourniquet pressure such that lower, effective pressures are employed , 26. OthBasic research and clinical studies have clearly demonstrated that higher tourniquet pressures are associated with higher risks of tourniquet-related injuries , 14, 30.Personalizing tourniquet pressures based upon a patient's LOP has been verified and validated to ensure an effective bloodless surgical field, while maintaining personalization of the applied tourniquet for each patient , 17, 29.Despite the evidence which demonstrates the use of LOP substantially reduces tourniquet pressures while being safe and effective, no respondent in the survey indicated that they set tourniquet pressure based on a patients LOP. Because basic research and clinical studies have shown the impact of lower tourniquet pressures and pressure gradients, and because biomedical engineering advances now allow this to be done safely, efficiently, and effectively in practice, investigation of the impact on outcomes with a view to optimizing tourniquet use may be timely.Basic research and clinical studies have clearly demonstrated that shorter applied tourniquet pressurization times are associated with lower risks of tourniquet-related injuries , 33–35. Minimizing applied tourniquet pressurization time reduces the risk of tourniquet-related injuries , howeverMeta-analyses focused on the sole question of “tourniquet or no tourniquet” use have led to limited, inconclusive, and conflicting results and conclusions. Future investigations may be better framed and advanced to ask more comprehensive questions about how or whether key tourniquet parameters might be optimized to retain the benefits of tourniquet use while mitigating the associated risks. Our survey demonstrated that there is a wide range of understanding and practice associated with tourniquet use in TKAs, and that while there is such variation, a general conclusion regarding the safety and efficacy of tourniquet use in TKA procedures is impractical. In order to advance this discussion, researchers of pneumatic surgical tourniquet use should include specific details regarding key tourniquet parameters when describing both methods and limitations of a study. Correspondingly, when meta-analyses of tourniquet use are published, they should include a comprehensive risk-benefit analysis of the association between key tourniquet parameters and patient outcomes, or at minimum clearly state that their conclusions are limited by the omission of key parameters.Our survey and associated discussions identify considerable variability in tourniquet use with respect to several key parameters, as well as a need for further research and updated guidelines regarding key parameters of safe tourniquet usage to optimize tourniquet use in Orthopaedics. We have outlined the mechanisms for operationalizing the results of basic science research and clinical studies by translating advances in biomedical engineering and adapting the characteristics of surgical tourniquets so that they can be readily employed in clinical practice. The individual key tourniquet parameters can and should be studied in order to optimize the use of tourniquets with a goal to retain the benefits and improve patient outcomes.