Navigating women's mental health between hormonal and social factors has only lately become a focus of research in our international psychoendocrinology community. Research had long been in men's hands; in female hands it started out stymied by contradicting forces—fear of losing the “gender race” in an honest view of biological differences between genders, most notably significant hormonal fluctuations during women's fertile years, vs. the urgent need to identify social parameters women require for well-being and fulfillment of potential, especially in times of hormonal transitions. Nowadays, gender problems for the average couple typically arrive with children and pressures to juggle motherhood and career. Unjust social-interactional patterns in gender roles could constitute a key factor for the significantly higher prevalence of depressive disorders in women vs. men. Stress resulting from social injustice has always compromised mental health. Women with a stress reactivity marked by trauma, either to themselves or (epi-)genetically transmitted, need our particular attention, and here first and foremost those women choosing motherhood next to a career yet lacking adequate support. Their vulnerability to falling into socially detrimental situations and further health problems may in turn lead them into a health service traditionally labeling them as psychiatrically ill or sexually dysfunctional when they are simply suffering from social-interactional injustice. Historically, mankind could have taken a fairer approach, addressing social-interactional stressors instead of additionally attacking female self-confidence by subjecting them to psychiatry. Lack of support to women has been identified as a highly relevant factor for women's higher prevalence of depression . Which women experience increased sensitivity to fluctuations in sex steroids  and stress-related steroids? We integrate both dynamics into the concept of “steroid hormone sensitivity” highlighting the role of psychosocial stressors with the aim of providing a theoretical basis for more integrative endocrinological, social and psychological treatment options and prevention strategies for susceptible women.Alongside new data we provide a thorough review of the key genetic, neuroendocrinological and social-interactional perspectives on the connection between hormonal fluctuations, stress and mental ill-health. McGuire et al. present data suggesting more advanced pubertal physical development and greater rejection sensitivity predicted higher levels of depressive symptoms later. Walsh et al. indicate the role of trauma finding that early life abuse increases effects of intranasal oxytocin on symptoms of premenstrual dysphoric disorder, highlighting the importance of examining women's social-interactional history for predicting hormonal responses. Leeners et al. investigate the association between estradiol, stress perception and stress-related cognitive performance during the menstrual cycle and fertility treatment. Poromaa et al.'s brain imaging study confirms low levels of Allopregnanolone relate to higher serotonergic binding in the prefrontal cortex, crucial to cognitive performance and top-down emotional regulation and the typical pre-ovulatory increase in female well-being.From puberty and the start of the menstrual cycle, the prevalence of depression in women rises dramatically. Melón et al. provide further insights into the role of neurosteroids via preclinical testing of a novel therapeutic compound for postpartum depression. Osborne et al. focus on pregnancy's second trimester Allopregnanolone as predictor of post-partum anxiety, which may precede depression. Kress et al. provide a glimpse into their multi-method cohort study protocol , contributing to greater understanding of the role of social, work and stress factors in mental and somatic health and its long-term endocrinological and transgenerational correlates within the family.Concerning peripartal mental health, Gordon et al. provide support for the hypothesis that perimenopausal estradiol fluctuations increase women's sensitivity to psychosocial stress and vulnerability to depression. Mernone et al. examine sexual health in aging women, showing age and postmenopausal status to be negatively associated with sexual functioning, but also that psychosocial factors such as emotional support are crucial to female sexual well-being. In Dickenson et al. we learn about the role of mindfulness in sexual arousal. They examine a potential oxytocinergic neuroendocrine mechanism underlying the link between mindfulness and sexual arousal by looking at subjective and oxytocinergic responses to mindfulness and correspondingly to sexual arousal.As to women's perimenopausal mental health in their pilot study To conclude this collection of articles, a simple question and potential answers—could the removal of the remaining psychosocial stressors for those women still living in patriarchally tinted structures (once again exemplified by the Covid-19 pandemic driving mainly mothers out of the workforce) be the most obvious first step to reduce the significantly higher prevalence of female depression? Let us revisit depression and anxiety as identifiers for unmet human needs due to social ills. Key solutions could be significantly improved societal responses to the female hormonal transitions framing human reproduction and aging and a clear view on requirements for good female sexual health, a fundamental pillar of stress-release for both sexes. A worldwide behavioral change might be required toward a fair management of biological differences between men and women, the ignoring of which has come to deteriorate female well-being in matching fulfillment from motherhood and career. Instead of supporting pharmacological profits from anti-depressants, benzodiazepines and hormonal treatments we could opt for increasing societal profits by applying these latest psychoendocrinological findings to lift psychosocial interactions between the sexes to the next level of social justice. Translations of research into practice are well under way as evidenced by new psychoendocrinology practices, psychoendocrinology courses in medical and psychological faculties and increasing societal awareness of such scientific insights. More to come!The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A longstanding body of literature reveals that experiences of discrimination and exclusion lead to health disadvantages by increasing physiological stress responses both in the body and the brain. However, a sociological view that takes into account structurally and culturally shaped biological processes is missing from the literature. Building on recent literature from the sociology of morality and values and the dual process model of culture, this paper proposes and provides preliminary evidence for an applied theory of culturally situated moral cognition as a coping mechanism with ethno-racial stress. I focus on values as they help cope with ethnicity and race related stress such as discrimination. Using functional neuroimaging data, I offer evidence that values operate through both explicit (controlled and conscious) processes recruiting brain regions like the dorsal prefrontal cortex, and implicit (automatic and non-conscious) processes recruiting regions like the ventromedial prefrontal cortex, to help cope with exclusion and discrimination. A longstanding body of literature reveals that experiences of discrimination lead to health disadvantages by increasing physiological stress responses such as blood pressure, cardiovascular reactivity and heart rate . HoweverThis paper argues that cognitive sociology and the newer research area “neurosociology” have the potential to add the literature on health disparities by linking micro and macro foundations and detailing the ways our minds and bodies reproduce social structure and inequalities . This neBuilding on a growing body of recent literature on moral and cognitive sociology e.g.,  and the Drawing from recent literature from the sociology of morality and values and the dual process model of culture and moral cognition , I propoFurthermore, as put forward by recent theorizing in sociology of morality , this paA large body of literature has focused on the effects of living in ethnically and racially diverse societies. This research suggests that while many civil rights have been extended to ethnic/racial minorities and communities are getting increasingly diverse, ethnic diversity is linked to detrimental individual and community outcomes such as decreased social trust and civic life (Putnam 2007). Furthermore, several studies show that ethnic/racial diversity has important connections with health outcomes, especially for minorities. Members of ethnic and racial minority communities show poorer subjective and objective outcomes of well-being and health. For example, African Americans report lower levels of subjective well-being (Thoits and Hewitt 2001), show increased obesity rates , hypertension prevalence  and even higher mortality rates  than their White counterparts in the US. There is a higher prevalence of mental health problems  among immigrants and refugees in the United States and other Western nations .Disparities in socio-economic status are proposed as a fundamental cause of health inequalities as lack of access to resources is linked to various diseases and higher mortality rates  and thus help explain ethnic/racial health disparities . A White ethnic group, Jewish Americans, rated their health lower than non-Jewish White Americans (Pearson and Geronimus 2011). White Americans report higher rates of depression than African Americans . Moreover, minority status predicts eudemonic well-being—having a purpose and meaning in life . Similarly, both first and second generation Turkish immigrants in Germany have lower mortality rates than  their German counterparts, a phenomenon not entirely explained by neither selection  nor attrition  effects . I suggeSociologists of culture and morality have been increasingly paying attention to values as core components of moral culture binding people and motivating behavior e.g., ; 1994. VWhile all humans share certain values to some extent see  theoriesBehavioral correlates of agentic values (such as self-enhancement or openness) usually hinge on taking charge and direction, influencing others behavior and opinions  but alsoCommunal values (self-transcendence vs. self-enhancement dimension) revolve around cultivating prosocial concern and interest for the welfare of others and the overall community over self or power related advantage. From an evolutionary point of view, the capacities for altruism, empathy and reciprocity and the associated emotional states provided an evolutionary advantage and added to the adaptive fitness of humans by maneuvering complex social organizations . People The implicit vs. explicit mechanisms of communal or agentic values  have not been investigated so far, leaving an important gap in identifying the mechanisms for coping with ethno-racial stress, which this paper addresses.This paper proposes that culture provides cognitive buffering resources for ethno-racial stress through two value mechanisms: one attenuating felt social pain via communal values and another providing more active and adaptive strategies to these difficult situations through agentic values see also . The limThe protective role of agentic values against the negative effects of ethno-racial interactions is also supported by some literature that mainly focused on psychological constructs such as self-esteem or vigilant coping. While these constructs are not value orientations, they are aligned with agentic orientation’s core dimensions such as being able to take charge and manipulate one’s surroundings; and, thus offer some insights into how agentic values might help cope with stress. Accordingly, research shows that self-esteem protects people from negative social threats and stress  through a vigilant coping style that seeks new, instrumental information and provides active and problem focused solutions in the face of ethno-racial stress and discrimination . For example, African American adolescents with higher self-esteem showed lower anxiety when faced with online discrimination than those with lower self-esteem . Furthermore, vigilant coping style diminished negative mental health outcomes among Korean immigrants in Toronto (Noh and Kaspar 2003) and African Americans . Attribution theory in psychology also offers some evidence suggesting that attributions about the causality and controllability of stigma and discrimination moderate well-being . Research directly focusing on values also supports these findings with cross-cultural survey data by demonstrating that openness to change value orientation enhances well-being .In summary, the literature on the social psychological processes of exclusion and inter-group contact have identified two important, seemingly juxtaposed, cultural cognitive resources: communal vs. agentic values . I suggest that these seemingly contradictory results can be reconciled through a dual cultural coping mechanism: 1) an implicit motivational coping attenuating felt social pain via communal values and 2) another explicit coping mechanism providing more active and adaptive strategies to these difficult situations through agentic values see also .In the proposed framework here, 1) communal values provide a sense of coherence and community that serve as collective resources promoting positive adjustment and resilience, while 2) agentic values contribute to being able to respond to the environment in novel ways by paying attention to previously ignored approaches to problem solving and enhancing effectiveness of coping. While the effects of these value systems on neurological responses to ethno-racial stress have not been directly researched so far, several other studies that focused on similar moderators or potential behavioral manifestations of these values have found evidence in this direction. For example, cross-ethnic/racial friendships reduced stress hormone reactivity in participants who were implicitly prejudiced or highly concerned of out-group rejection , predicted faster recovery from stress-related respiratory and hormonal reactivity , and these positive effects were carried on to interactions with novel other-ethnicity members . Similarly, several factors such as secure attachment style , essentialist beliefs about groups, perceptions of discrimination , essentialist beliefs about groups , racial group membership and implicit bias (Krill and Platek 2009) were also found to be moderating neural responses to social exclusion and inter-racial contact. Therefore, I expect communal and agentic values to reduce sympathetic (“fight” or “flight”) stress responses such as respiration, heart rate and skin conductance and increase parasympathetic responses that prepare the body to return to the homeostatic state like increasing heart rate variability through recruiting different brain regions for explicit and implicit coping.Sympathetic and parasympathetic nervous systems are both components of the autonomic nervous system, which regulates the automatic and mostly non-conscious activity of the body. While sympathetic nervous system responds to stressful or physically arousing situations (aka “fight or flight” response) by increasing skin perspiration, respiration and heart rate, parasympathetic nervous system calms the body down or is involved in regular/ordinary activity such as slowing heart rate and respiration. These responses are down or up regulated (through feedback loops) by the central nervous system activity in the brain.Relying on a functional dissociation in the human prefrontal cortex see , and faiThe dlPFC is the center for executive, top down functioning and goal directed behavior with connections to the temporal and parietal cortices to receive visual, somatosensory, and auditory information and the motor areas of the brain to coordinate movement .Based on this functional dissociation between the vmPFC and the dlPFC, I argue that we can identify the dissociable mechanisms for cultural coping strategies in response to ethno-racial stress in the human brain as 1) increased activation in the ventromedial prefrontal cortex  ball tossing game between two or more players represented with animated gifs  and has been widely used for research on ostracism, social exclusion, or rejection . As in previous Cyberball studies, participants were told prior to scanning that we were interested in “mental visualization” ability , and that they would play a game of catch over the internet with two other players. They were instructed to imagine the experience as real as possible. In this game, social exclusion was simulated with inclusion or exclusion from the game with ball tosses. There were a total of three runs . At the beginning of each run, the participants read a short paragraph describing three almost identical stories describing a trip to the city, beach or the countryside with equal number of pronouns and gave their answer on a screen with a finger key response. This cultural priming procedure, also referred to as the “pronoun circling task” has been shown to effectively prime agentic  or communalistic (collectivistic) values in a number of previous behavioral as well as fMRI studies . All priming conditions contained identical stories, except for the following target phrases: I, my, me for individualism; we, our, us for collectivism; and they, their, theirs as a control/comparison condition . In the inclusion condition, the participants were over-included  in order for them to register systematic differences between the inclusion and exclusion conditions and for the exclusion condition they were partially or completely excluded . Each block lasted 24 s, followed by a fixation cross (16 s) see . The ordData were first analyzed as individual level data and then combined into group level analyses on individual statistics. Data analysis presented here includes region of interest analyses (ROI) (for vmPFC and dlPFC brain regions) using AFNI  software. For each functional run, data were preprocessed to remove sources of noise and artifact. Data were corrected for differences in acquisition time between slices for each whole-brain volume, realigned within and across runs to correct for head movement, and co-registered with each participant's anatomical data. Normalized data were then spatially smoothed. Then, a deconvolution analysis was used to extract a hemodynamic response function for each subject. The effects of the conditions were modeled by box-car regressors convolved with the hemodynamic response function for 24 s for blocks of each trial type. Motion correction parameters were included as nuisance covariates and TRs with motion derivatives exceeding the Euclidian norm of 0.4 mm were censored in deconvolution analysis. Group-level analyses on the hemodynamic response estimates from individual statistics were conducted with a three way  Multi-Variate Modeling Approach (AFNI’s 3DMVM command) that applied ROI masks for dlPFC and vmPFC.A, there is greater vmPFC activation during communalism (vs other) and exclusion (vs inclusion) contrasts and greater dlPFC activation in agentic  and exclusion (vs inclusion) contrasts in Black (vs White) respondents. This empirical illustration provides preliminary evidence for two potential mechanisms, one implicit and the other explicit, for the ways values might help racial minorities cope with the effects of social exclusion. These contrasts do not necessarily indicate that White respondents in the sample did not show similar responses. It simply meant that for Black respondents the findings were stronger. This makes sense given the context and history of United States race relations where marginalization, oppression and systemic exclusion of Black folk are hardened into the social fabric, causing a stress and anxiety overload.In This paper seeks to advance current understandings of cultural and cognitive sociology and the dual process models through uncovering the ways in which values can attenuate responses to social exclusion through influencing implicit and explicit neurological processes. Recent research on dual process models has rejuvenated the interest on methodologies that go beyond traditional ethnography or survey methods to capture implicit and automatic cognitive and emotive processes of culture  discrimination and systematic social exclusion situate members of ethno-racial minority groups into oppressed and marginalized positions in the social hierarchy, values might serve as cultural, collective resources that can help improve resilience in the face of stressors. In this framework, values act as “a key cognitive capacity that can act as a mental resource for communities of color” : 77. If In conclusion, this paper has important implications for identifying the biomarkers for coping styles in response to ethnicity related stress by focusing on a sociological mechanism that operates both at the individual and macro level: value orientations. Previous research has focused on personal backgrounds such as previous racial contact or cross-ethnic friendships or psychological attributions such as self-esteem; but, no research has explored the macro societal and cultural dimensions underlying coping strategies at the micro level. The logical next step in this research paradigm would be to connect these neurological mechanisms with physiological stress responses to demonstrate the culture-brain-stress link. Responses to social interactions including ethno-racial interactions are bodily and cognitive phenomena; they are experienced and enacted through our bodies and our brains. Traditional experimental techniques like behavioral responses or survey methods are indirect ways of measuring these cognitive and bodily processes. Coupling brain imaging data with physiological data would be a spearheading attempt in linking biological mechanisms of ethno-racial relations to sociological understandings. Hopefully, this paper was able to offer a neurosociological research framework for future research seeking to expand our understandings of stress mechanism and response to social exclusion as they relate to value based coping strategies.


Fakuade ,,Postoperative atrial fibrillation (AF) is a frequent and burdensome complication in patients undergoing coronary revascularization and heart valve surgery. Whilst it is recognized that haemodynamic stress and the inflammatory response associated with cardiac surgery may play an important role in triggering the arrhythmia, patients with a diagnosis of postoperative AF who are discharged from hospital in sinus rhythm are more likely to develop AF and ischaemic stroke on long-term follow-up.,To date, atrial electrical remodelling and fibrosis have been a main focus of research in AF, even though both factors are more robustly identifiable as a consequence rather than a primary cause of AF. In contrast, large prospective cohorts have identified impaired left atrial function (i.e. a lower emptying fraction) in individuals in sinus rhythm as an independent predictor of incident AF and ischaemic stroke.Cardiovascular Research, Fakuade et al.In this issue of Based on our current knowledge of the mechanisms regulating intracellular calcium handling in cardiomyocytes, one could easily identify a number of ‘usual suspects’ that may account for this phenotype, some of which were swiftly acquitted. For instance, differences in postoperative heart rhythm were not associated with changes in peak and overall calcium influx through the L-type calcium channel  or with differences in intracellular calcium buffering properties, t-tubule density, sodium-calcium exchanger (NCX) function or sarcolemmal calcium ATP-ase activity. Importantly, differences in ryanodine receptor (RyR) phosphorylation or calcium leak did not account for these findings.A slower rate of intracellular calcium decay in paced cardiomyocytes in the absence of differences in NCX function would point to a reduced SR calcium-ATPase (SERCA2A) activity. SERCA2A is the master regulator of intracellular calcium cycling and its activity is chiefly responsible for the rate of calcium reuptake in the SR, which in turn influences the calcium buffering reserve of contractile proteins and the intracellular calcium stores, and plays an important role in both cardiomyocyte contraction and relaxation, particularly under unloaded conditions.,The relationship between SERCA2A activity and arrhythmia is more complex and may vary depending on concomitant changes in diastolic calcium and the threshold for SR calcium leak/release from the RyR. In previous publications, SERCA2A activity has been reported to be higher in atrial myocytes from patients with postoperative or paroxysmal AFCould these changes in SERCA2A protein content, in the absence of proportional differences in total and phosphorylated phospholamban, be sufficient to explain the reported abnormalities in intracellular calcium handling? Whilst the findings cannot conclusively prove or disprove that is the case, the authors duly noted that, in addition to phospholamban, SERCA2a activity is modulated by a host of other proteins,in silico and demonstrated experimentally. Alternans in cardiac myocytes typically manifests as fluctuations in action potential duration, calcium transient amplitude, and contraction amplitude. Both in silico models and clinical investigations have shown that cardiac alternans may play an important role in the initiation and maintenance of AFIn the absence of an increase in diastolic calcium and RyR calcium leak, how might a reduction in SERCA2A activity promote postoperative AF? The authors suggest this may occur through the promotion of calcium transient and action potential alternans, as predicted Whilst a lot has been learnt from studying atrial myocytes isolated from samples of the right atrial appendage taken before cardiopulmonary bypass, postoperative AF occurs after reperfusion when local and systemic oxidative stressHumans are the ultimate ‘model’ of postoperative AF and the authors are to be commended for collecting data from a large number of patients. Yet, even the ultimate model is prone to limitations that are also visible in this study, some of which are unavoidable; e.g. small tissue samples precluding the attainment of matched data for related mechanisms, as illustrated in Online Figure 1. Others, such as the large variation between patients and in the success of cell isolation could have been mitigated by the use of more advanced statistics.et al.In summary, in a series of carefully conducted experiments in human atrial myocytes Fakuade BC is funded by the British Heart Foundation (CH/12/3/29609).Conflict of interest: none declared.


Invertebrate antimicrobial peptides (AMPs) are at the forefront in the search for agents of therapeutic utility against multi-resistant microbial pathogens, and in recent years substantial advances took place in the in silico prediction of antimicrobial function of amino acid sequences. A yet neglected aspect is taxonomic bias in the performance of these tools. Owing to differences in the prediction algorithms and used training data sets between tools, and phylogenetic differences in sequence diversity, physicochemical properties and evolved biological functions of AMPs between taxa, notable discrepancies may exist in performance between the currently available prediction tools. Here we tested if there is taxonomic bias in the prediction power in 10 tools with a total of 20 prediction algorithms in 19 invertebrate taxa, using a data set containing 1525 AMP and 3050 non-AMP sequences. We found that most of the tools exhibited considerable variation in performance between tested invertebrate groups. Based on the per-taxa performances and on the variation in performances across taxa we provide guidance in choosing the best-performing prediction tool for all assessed taxa, by listing the highest scoring tool for each of them. In the last few decades, invertebrates (mainly arthropods) have become central model organisms to identify and classify novel AMPs with potential utility in medicine5. With the rapid accumulation of available genomic and proteomic data from a wide range of taxa and novel methods for the prediction of structural, physicochemical, and biological properties of peptides, the search for therapeutic-potential AMPs is one of the most exciting and promising areas in the life sciences7. In fact, by today a considerable number of AMP activity prediction tools has been built, mainly utilizing modern machine-learning algorithms to identify amino acid sequences with potential antimicrobial capacities, generally on the basis of their physicochemical parameters8. Most often these parameters are some combinations of net charge, hydrophobicity, amphipaticity, isoelectric point, propensity to form certain structures , polarity, and hydrophobic moment10 and sometimes quantification of amino acid composition itself , which properties are associated with the capacity to attach to pathogen-specific targets .Antimicrobial peptides (AMPs) are low molecular weight components of the innate immunity present virtually in all living organisms. Their importance has long been recognized, especially in the search for efficient therapeutic agents against multi-resistant bacteria12 and references therein), neglected taxonomic  information may also contribute to biases in the training of prediction algorithms. Although AMP prediction tools are quite available, and some articles made attempts of benchmarking how efficiently these tools can identify AMPs in general (e.g.13), it still remains overlooked whether or not these prediction tools may provide the same performance across the taxa from which putative AMPs are extracted. This could be rather problematic, owing to that even among phylogenetically related AMPs substantial differences may exist in the evolutionary trajectories of the amino acids between species. For example this might be expected to lead to differences in taxon-specific gene clustering , or in the evolved functionality of peptides belonging to the given AMP family17. Indeed, the importance of evolutionary origin of sequence diversity in these molecules was emphasized recently in invertebrates18. While there is little knowledge about how such diversity may be associated with physicochemical properties and structural features of AMPs, it is not unreasonable to assume that unaccounted taxon-specific variation in them might affect the performance of prediction tools in recognizing antimicrobial function . Also, alternative tools using different methodological approaches and training sets further complicate the picture and may lead to discrepant performances, i.e. to differences between the prediction tools in how efficiently they recognize AMPs and non-AMPs in different taxa, which might depend on the taxonomic composition of the training data sets. In other words, the above mentioned factors may play a role in a low generalization-efficiency of the prediction algorithms that were trained on taxonomically  limited training data set. Consequently, neglecting this aspect may lead to an increased incidence of both type I  AMPs) and type II  errors when using inadequate tools.Beside to other challenges of AMP prediction using peptides from databases , a practical resolution (in terms of the usage of available prediction tools) could be the identification of which tool performs best for specific taxa, and consistently using these tools in the given groups. As a first approach to address this problem, taxon-specific assessment of the performance of currently available AMP prediction tools may help us to shed light on whether or not a taxon-bias is present at all. Accordingly, in the present study our aim is not to provide a comprehensive list of AMP prediction tools, or to introduce their algorithms and/or modern methods for AMP prediction, but to provide guidance in choosing the best-performing prediction tool for specific taxa if taxonomic bias exists. In other words: our goal here is not to present the methodology and specific composition of training data sets in detail, but to assess whether currently available tools show considerable prediction bias between different invertebrate taxa, i.e. we do not yet offer a specific solution to this technical problem at the level of algorithms, but highlight a yet neglected aspect of AMP prediction practice.This issue is anything but trivial, as a wide range of researchers rely on these AMP prediction tools and their outputs, from the search for invertebrate AMPs with therapeutical potential21 and the Antimicrobial Peptide Database APD322) and 3050 non-AMP sequences (from UniProt23), from 19 invertebrate taxa, and used 10 freely available AMP prediction tools , not only to assess the prediction tools’ overall performance, but their performance per taxa.To do so, we acquired 1525 unique AMP sequences , and to iAMP-2L  the non-artificial-neural-network algorithms of CAMPR3  showed weakest performances.Overall ADAM showed the best performance with both of its algorithms . Also, the artificial neural network classifier of CAMP-2L Fig. . Based oR3 and in the linear kernel CS-AMPpred , and positive bias for Xiphosura and Araneae (meaning that for these groups F1 and MCC scores were consistently high across prediction tools). In taxa for which sample sizes were small (such as Unionida and Neogastropoda) this bias might simply be an artefact of chance, as any given prediction affects the estimated performance score much stronger than in taxa of larger sample sizes. However, in Veneroida and Araneae the sample sizes were not quite small, and in other small-sample-sized taxa no such pattern was observed. At this point it is difficult to find a satisfactory explanation for this observation. Given that most of the tested tools rely on amino acid sequence-based physicochemical measures, one possible cause might relate to the similarity of amino acid sequences in a given taxon to those used in the training sets of prediction tools. For example, even if a given taxon is not represented in a tool’s training set, similar physicochemical properties to the training sequences likely helps better recognition by the given tool. On the other hand, if physicochemical properties of a given taxon are significantly different from those taxa included in the training set, it will likely lead to poorer performance for that given query taxon not represented in the set. This should be addressed in future studies to clarify what mechanisms can lead to such biases in prediction performance.In most cases taxonomic biases were tool specific, meaning that there were only a few taxa for which most of the prediction tools yielded consistently low or high performance Fig. . Specifi12), sequences are classified based on their resemblance to known AMPs. Notably, such an approach may yield null-findings when presented a previously unknown AMP, but might potentially enable for accounting for evolutionary information. Although the hidden Markov model ADAM tool technically does not consider phylogeny for the taxa from which the query sequences originate, in future prediction tools homolog  finding may be a quite useful approach in the reliable in silico identification of AMPs. Surprisingly, tools accounting for  evolution are still lacking, and studies addressing the question of functional typization of AMPs generally use amino acid composition12, and/or quantitative structure–activity relationships24. Whilst understanding the association between sequence, structure, and biological function is indisputably the forefront in the study of AMPs with therapeutical potential26, evolutionary information may also help us in the identification  of candidate AMPs. Arguably, a taxonomically, or even phylogenetically informed perspective would be quite useful not only in the more robust and reliable identification of AMPs in invertebrates, but also in designing and engineering peptides with desirable properties , through a deeper understanding of how different antimicrobial properties evolved in AMPs of invertebrates.  Hence, comparative phylogenetic analyses of AMPs would be an important aspect helping to understand the evolution of antimicrobial function in these molecules.The prediction tool ADAM using the hidden Markov model provided the best performance in most assessed taxa. While it is out of scope of this study to give in-depth insights on the algorithms behind the prediction tools, it should be noted that this tool’s strength likely comes from its set of homologues: it uses a probabilistic model based on which the already known AMPs are used to find the most likely homologue for the query peptide. This is a strength that few currently available prediction tools possess, namely that, instead of only using scalar physicochemical properties based on the amino acid sequence  may have quite different physicochemical propertiesWe argue that our results can provide a firm basis for deciding which prediction tool(s) to use when working with invertebrate peptides. Joint consideration of tools’ performance and taxonomic bias may help to pick the best tools: for example, when one would like to test peptides of multiple taxonomical origins, it might be worth to consider tools with relatively low taxonomic bias and good performance, whereas when peptides originate from one known taxon, tool-specific performance in that group will be more important than the generalization capability of the given tool.1 and MCC scores and prediction successes are more likely to be subjected to distortions by random chance than in taxa of larger sample sizes. Still, we think that as a practical guide our results are still of value even for taxa with small sample sizes, although with more caution. Secondly, one could propose that overlap between our test data set and training sets of prediction tools might also bias our performance estimates. However, we found no strong evidence for that, since neither the number nor the proportion of common amino acid sequences in our and the used tools’ data sets showed significant association with F1 scores, although the proportion of common sequences showed a weakly significant association with MCC  F1 and MCC scores tended to be slightly smaller  that have available sequence data for a wide range of taxa might help improve the performance of new prediction tools.Additionally, due to the variable availability of AMP sequences for the different taxa, AMP family could not have been included when testing performance, even though there might be tool-specific differences in it for the different AMP families (i.e. a given tool may differ in its capacity to recognize defensins versus cecropins as AMPs). Notably, we know about no studies explicitly assessing the effect of AMP family on the efficiency of AMP prediction, therefore this aspect might be a quite relevant and important one to address in future studies. Furthermore, owing to practical reasons, non-AMPs  are not standardized, i.e. these peptides are generally drawn randomly from those peptides that are available for the given taxa, with no known functions in antimicrobial immunity. Indeed, both in training and benchmarking data sets, false negative samples may be present in the form of yet-unknown (or simply undocumented) antimicrobial activity of some proteins used in the negative  data sets. Also, non-overlapping biological functions between peptides from different taxa might introduce additional bias in the performance of prediction tools. For example, some membrane-active peptides might be expected to be falsely recognized as AMPs more often than others, due to their structural and physicochemical properties similar to that of AMPs30). Indeed, more reliable and robust in silico prediction tools utilizing modern algorithms and ever larger data sets undoubtedly require standardization of quality of data. As such, AMP records could contain biologically and clinically relevant informations about the given peptides . Similarly, standardized sets of non-AMPs characterized by laboratory-confirmed absence of antimicrobial activity in relevant contexts , and/or model organisms would quite likely help us improve current and future prediction tools and AMP design.Although our current study addresses in silico prediction of antimicrobial activity in (invertebrate) peptides based on amino acid sequence, some of the details we have discussed are connected to the recent aspiration to improve upon currently used methodological standards of (pre)clinical testing of AMPs  in prediction performance of the assessed tools is outside the scope of our paper, and we are not able to offer technical details or solutions. We merely aimed to highlight an overlooked phenomenon, and to provide a practical guide to use the currently available and most popular tools. We hope that our results will serve as a useful guide in choosing the appropriate AMP prediction tool for testing candidate peptides in invertebrates to a wide range of researchers. This could be useful for the big-data/bioinformatic data style search for candidates in open databases and repositories, and for the identification of AMPs in invertebrates for ecophysiological studies as well. In the search for putative AMPs based on genomic and/or proteomic data, and immune profiling based on transcriptomics (i.e. screening produced peptides using transcriptome) in invertebrates may also benefit from our proposed approach. In addition, future studies to implement refined AMP prediction techniques, inclusion of taxonomic and/or phylogenetic information, utilization of explicit categorization of AMPs, and standardized sets of non-AMP sequences will undoubtedly help us to achieve more robust prediction of antimicrobial function in invertebrate models throughout our endeavour to identify peptides of potential therapeutical utility.32. AMP sequences were acquired from the protein database of the National Center for Biotechnology Information21 and the Antimicrobial Peptide Database APD322  = 63, Q75 = 95, Qmax = 452.All data handling and analyses were performed in the R software for statistical computing (ver. 4.0.1)23: for each taxon, a large batch of proteins without known antimicrobial activity was acquired, between the length of 10 and 200 amino acids . Results from the prediction tools were evaluated using the typical binary classification performance measures:1 scores can range between 0 and 1, the former indicating that either sensitivity and/or precision is zero, whereas the latter indicates perfect precision and sensitivity. Furthermore, we have calculated Matthew’s correlation coefficient (MCC) as well, using the R-package “mltools”41. MCC was found to be unbiased in imbalanced confusion matrices in binary classification, and was suggested to be adopted as the standard performance measure in the evaluation of binary classification tasks42. MCC values range between − 1 and 1: larger positive values reflect better prediction, zero indicates prediction no better than random chance, and negative values indicate consistent disagreement between prediction and observation. In our evaluations and analyses we decided to report both F1 scores and MCC, because F1 is still widely used and a large number of researchers may find it helpful to see both performance measures while interpreting our findings.F1 score and highest MCC for each specific taxon. We also presented all scores for all tool-taxon combinations (see “Tool performances were also assessed separately for taxa. When inferring on the best performing tool for each taxon, we used the “highest score” rule of thumb, and we listed the prediction tools both with the highest Fons see “”. AdditiSupplementary Information.


This scoping review explores how virtue and care ethics are incorporated into health professions education and how these factors may relate to the development of humanistic patient care.Globethics.net, Philosopher’s Index, and ProQuest Central) lending themselves to constructs of humanism curricula. Our exclusion criteria consisted of non-English articles, those not addressing virtue and care ethics and humanism in medical pedagogy, and those not addressing aspects of character in health ethics. We examined in a stepwise fashion whether citations: 1) Contained definitions of virtue and care ethics; 2) Implemented virtue and care ethics in health care curricula; and 3) Evidenced patient-directed caregiver humanism.Our team identified citations in the literature emphasizing virtue ethics and care ethics (in PubMed, NLM Catalog, WorldCat, EthicsShare, EthxWeb, Eight hundred eleven citations were identified, 88 intensively reviewed, and the final 25 analyzed in-depth. We identified multiple key themes with relevant metaphors associated with virtue/care ethics, curricula, and humanism education.This research sought to better understand how virtue and care ethics can potentially promote humanism and identified themes that facilitate and impede this mission. Health care education in the last two decades has led many to grapple with the means of better understanding professionalism in medical education . The ProWe seek to identify health care curricula using virtue and care ethics and how humanistic behavior is thereby promoted. Virtue ethics is one of three major ethical theories on how one should respond to moral quandaries. Virtue ethics emphasizes how optimizing those aspects of moral character will predispose one to behave in an ethical manner and has been frequently described as core to professionalism . The othCare ethics at its core is relational , 51 and “Humanism in healthcare is characterized by a respectful and compassionate relationship between physicians, as well as all other members of the healthcare team, and their patients. It reflects attitudes and behaviors that are sensitive to the values and the cultural and ethnic backgrounds of others”  OR virtues OR “virtue ethics” OR Caring [Mesh] OR “care ethics”) AND (“Humanism”[Mesh] OR humanism) AND ).We emulated the Scoping Review method articulated by Levac  to evalufull text searching of our search terms within the abstracts of each identified citation. As shown in Fig. Globethics.net (2004 -), Philosopher’s Index (1986 -), and ProQuest Central (1986 -), which incrementally added to the critical mass of resultant articles (by MD). Searches were initiated with PubMed on December 19, 2017, with subsequent stepwise additions utilizing the other identified databases through October 3, 2018.Our team identified the literature in ethics highlighting those aspects with an emphasis on Virtue Ethics and Care Ethics, first in PubMed 1972 -). Despite using the Boolean “OR” for keywords and PubMed Mesh terms for maximum inclusivity, we noted a grave paucity of articles with our first PubMed search query. Thereafter, we employed PubMed’s unique database feature of 972 -. Denon-English articles, those not addressing the use of virtue and care ethics toward humanism in medical curricula, and those not addressing aspects of character in health ethics.Our exclusion criteria consisted of: Have a well-accepted definition of virtue or care ethics? Describe how virtue or care ethics are implemented in a healthcare curriculum?Describe curricular efforts that contribute to patient-centered caregiver humanism?We read and analyzed eligible articles in a stepwise fashion, considering iteratively the following three requisite considerations “Does this paper…:”at leasttwoof the three factors were present: definition, curricular inclusion, and evidence of humanistic behavior as an outcome. The resultant 40 relevant papers were subjected to intense analysis by each team member. Each paper was scored on a four-level relevance scale . Inclusion was based on the majority of team members scoring the article as moderate or high. Each team member identified relevant themes and metaphors that were then discussed by conference call pertaining to virtue/care ethics, curricula, and humanism education. Differences in scoring of these 40 papers were minimal and negotiated by all team members via conference call, until we achieved consensus on 25 papers.Five hundred twenty articles were identified and evaluated using PubMed, with other ancillary databases yielding 246 additional articles, and 15 supplemental papers considered through citation referral yielding a total of 811 papers being screened. Team members DD, DO, MD, JdG, and BC evaluated the titles and abstracts of all papers. An initial review found 88 papers having at least one of the three sought factors. Next, papers were included only if implemented curriculum either proposed a curriculum or argued for curricular change.As depicted in Fig. The distinctive quality of these eight papers is that each lays a foundation of the conceptual framework of either virtue or care ethics and builds upon that basis with a curriculum that identifies humanistic outcomes. These papers emphasize multiple venues for virtue or care ethics — in undergraduate and graduate medical education, as well as in faculty development promoting mentorship — and as such, provide instructive templates towards future curricular development in this area.Academic Medicine had the largest number of publications, with the Journal of Medical Ethics following, and then a distribution between other medical ethics and health service journals and publishing houses. We next proceeded to identify relevant themes.The 25 articles range in date from 1994 to 2017, starting in proximity to when Gold Foundation Humanism efforts to foster humanism began and flourished, and when professionalism as a competency was introduced in US medical education assessment with one publication cluster noted in 2005–2009, and another cluster in 2015–2016. The journal Noteworthy Considerations that were identified and were coherent but not centrally on point as a theme of cultivating virtue/care ethics and humanistic behavior  in ethical cases to improve understanding . Some arThe theme of Relationships describes how virtue/care ethics are based upon the character-based interaction of two or more persons, although care ethics emphasizes the inequality of the relationship-based interaction. This theme notes how relationships foster care in medicine through humanistic practice in the caring endeavor . Each prThe theme of Praxis/Humanistic Behavior concerns the ways in which the learner may come to manifest humanistic behavior when incorporating the needed virtues and care in healing. Perhaps first described by Peabody nearly a century ago , virtue The theme of Culture/Hidden Curriculum addresses how deleterious aspects of medical culture  can upend humanistic educational efforts . This thThe identified noteworthy considerations of professionalism, narrative, burnout prevention, and learning communities, can be interpreted as additional means to counter impediments that adversely influence the cultivation of humanistic behavior. Professionalism is relevant in this scoping review as the aspirational intent of virtue and care ethics are professional development to overcome the detractive aspects of medical education that negatively affect behavior. Professionalism is cited by many papers as an application of virtue ethics to the medical social contract, based on altruism and contract keeping . ReflectThe consideration of Narrative describes the modality of teaching using narratives on physician virtues, motivations, and behavior looking at literature (rather than physician-life stories) to encourage compassion . Others The consideration of Prevention of Burnout specifically focuses on burnout prevention by focusing on relationships with patients, open discussions on burnout, and the challenges of suffering patients . LearninWhen the articles were evaluated for relevant metaphors Table , these chumanism, care ethics, and virtue ethics so that manuscripts could be discovered in our search. Of note, when we attempted to use professionalism, it did not alter our results. Our resultant list of citations was from reputable journals of medical education and ethics and worth consideration for future curricular development. What we can hope for now is a growth of more peer-reviewed articles that flesh out understanding of virtue and care ethics and recognize their differences. That is, virtue ethics has a focus on the individual character of the physician, whereas care ethics highlights interdependence, which may foster communities of practice to support resilience and personal growth [This scoping review is innovative with a specific goal of identifying thematic connections between virtue and care ethics, medical education, and humanistic clinical practice. While virtue ethics goes back to the time of Plato and Aristotle , its Renl growth . Such meThis scoping review set out to evaluate publications in the medical literature that address aspects of virtue and care ethics in medical curricula toward the cultivation of learner humanism. We successfully found twenty-five papers that were relevant, of which eight had full implementation through curricula. The themes noted assist in understanding the many factors that play a role in using care and virtue ethics in curricula toward humanistic behavior. It is the intention of this working group to encourage others to initiate model curricula that play off the strengths of the results of this paper to translate virtue and care ethics into a curriculum that promotes humanistic behavior. These published resources and the present analysis of them may serve as a foundation for sound curriculum related to humanism. Implementation will assist in utilizing virtue and care ethics and promoting humanism among physicians.


Minimally invasive procedures that directly deliver heat into tumors are commonly used to treat a wide range of malignancies. In this review, we discuss the potential role that these procedures can play in not only destroying small tumors but also educating the immune system to recognize and attack tumors throughout the body.Thermal ablation is a cornerstone in the management of cancer patients. Typically, ablation procedures are performed for patients with a solitary or oligometastatic disease with the intention of eradicating all sites of the disease. Ablation has traditionally played a less prominent role for patients with a widely metastatic disease. For such patients, attempting to treat numerous sites of disease compounds potential risks without a clear clinical benefit and, as such, a compelling justification for performing an intervention that is unlikely to alter a patient’s clinical trajectory is uncommon. However, the discovery of immune checkpoints and the development of immune checkpoint inhibitors have brought a new perspective to the relevance of local cancer therapies such as ablation for patients with a metastatic disease. It is becoming increasingly apparent that local cancer therapies can have systemic immune effects. Thus, in the new perspective of cancer care centered upon immunologic principles, there is a strong interest in exploring the utility of ablation for patients with a metastatic disease for its immunologic implications. In this review, we summarize the unmet clinical need for adjuvant interventions such as ablation to broaden the impact of systemic immunotherapies. We additionally highlight the extant preclinical and clinical data for the immunogenicity of common thermal ablation modalities. Thermal ablation is a cornerstone in the management of cancer patients . Both heOver the past decade, however, this conventional wisdom has begun to evolve due to the recent renaissance in cancer immunotherapies. The discovery of immune checkpoints and the development of immune checkpoint inhibitors has revolutionized treatment algorithms across the cancer spectrum . These aImmunotherapy represents a major disruptive innovation in cancer care. While immunotherapies such as systemic cytokines have been used clinically for decades, the field has recently undergone a revolution with the advent of immune checkpoint inhibitors. Immune checkpoint blockade antibodies that augment the effector T cell activity by blocking inhibitory molecules such as programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have achieved unprecedented advances in numerous cancer types . The outDespite paradigm-shifting advances in several malignancies, current immunotherapy approaches are limited in several ways. These limitations are well-exemplified in the case of a hepatocellular carcinoma (HCC), a malignancy that is commonly treated with ablation. An HCC is the third most common cause of cancer-related deaths globally and in the United States it is the fastest growing cause of cancer-related deaths . For patThere is a strong rationale for immunotherapy in an HCC. Patients with HCC tumors expressing high levels of PD-L1 have a significantly poorer prognosis than patients with a lower expression and the tumor expression of PD-L1 is an independent predictor for post-operative recurrence in patients with an HCC . Phase IBeyond the intrinsic immunosuppressive nature of an HCC, the liver itself can serve as a “trap” for tumor-specific T cells. Yu et al. demonstrated in multiple mouse models as well as in patients that liver tumors sequester T cells from the circulation leading to T cell killing in a macrophage-driven mechanism. This diminishes the efficacy of immunotherapy not only within the liver lesion but also for other tumors across the body. The study also found that patients with liver metastases have diminished circulating T cells compared with those patients who do not have  liver meA major question in immunotherapy, therefore, is how to broaden treatment responses to a greater proportion of HCC patients. The answer lies in combination regimens that modify the tumor microenvironment to potentiate the immunotherapy drug as recently demonstrated by the IMbrave150 trial that combined an anti-PD-L1 antibody with an anti-angiogenesis antibody . These nThe identification of resistance mechanisms to systemic immunotherapy for HCCs has been replicated for multiple other cancer types. Unfortunately, the objective response rates to checkpoint inhibitor therapy remain below 50% across all malignancies . Thus, wAn understanding of the mechanisms of systemic immunotherapy resistance requires an appreciation for the necessary steps to activate the adaptive immune response. It has long been appreciated that not all forms of cancer cell death are equal. Several forms of cell death initiate the immunogenic cascade of APC activation and T cell stimulation, clonal expansion and tumor eradication; such forms of cell death are termed immunogenic cell death (ICD). However, other forms of regulated cancer cell death can lead to T cell anergy and immune tolerance, thus inhibiting an anti-tumor immune response. Therefore, there is great interest in understanding the various forms of cell death that occur following local cancer therapies and prioritizing those modalities that result in ICD over other forms of regulated cell death; combining such modalities with systemic immunotherapies has the potential to greatly broaden the applicability of immunotherapy regimens for cancer patients.A recently published consensus guideline  detailedWhereas antigenicity classically arises from highly immunogenic microbial proteins or microbe-associated molecular proteins (MAMPs) not covered by central tolerance or exceptionally in healthy cells via stress-induced post-translational modifications or the activation of human endogenous retroviruses, cancer cells generate immunogenic antigens largely due to their high rate of mutation . Two majSeveral factors contribute to the successful generation of an immunogenic antigen such that only a fraction of mutations result in one. For example, the mutational burden of a tumor, which is heterogenous between patients and even within a patient across space and time ,22, playAblation is advantageous as a cancer therapy in this regard as it causes cell death and the release of antigens perhaps otherwise not adequately presented. Additionally, such extracellular antigens can be sampled by dendritic cells and presented on MHC class II complexes . While tComprehensive reviews of DAMPs mechanistically linked to cancer have been reported elsewhere ,35. BrieWnt-β-catenin pathway [There is considerable evidence that hyperthermia potentiates the adjuvanticity of tumor cell immunogenicity; for example, by the release of many of the aforementioned DAMPs (reviewed in detail in subsequent sections). Several of the immunostimulatory effects of hyperthermia on the tumor microenvironment include an increased tumor perfusion and reoxygenization allowing for an enhanced immune-effector uptake and a decreased hypoxia-related immunosuppression, an increased immune cell trafficking and effector function and increased pro-inflammatory cytokines ,39. Furt pathway .The generation of ICD has been identified in multiple locoregional cancer therapies including radiation therapy , direct Radiofrequency ablation (RFA) has been used in the clinical arena for decades; accordingly, the preponderance of evidence regarding immune activation following hyperthermia can be found in the RFA literature. In the preclinical setting, multiple studies have demonstrated that RFA releases numerous DAMPs including RNA, DNA, heat shock proteins and uric acid; furthermore, there is an elaboration of immunogenic cytokines including interleukin-1b (IL-1b), IL-6 and IL-8 ,52,53,54Evidence of systemic tumor immunity following RFA has also been identified in animal studies. Dromi et al.  evaluateContrasting the evidence of increased anti-tumor immunity following RFA is the identification of increased immunosuppressive markers. For example, we  and otheSuch combination strategies have been explored in both the preclinical and clinical setting. In a retrospective study, Shi et al.  reviewedCombining RFA with checkpoint inhibition has also been evaluated in a prospective clinical trial. In a single arm study, 32 patients with an HCC were treated with the CTLA-4 inhibitor tremelimumab and also underwent a subtotal RFA of the liver tumor . No doseMicrowave ablation (MWA) typically results in larger ablation zones in a shorter amount of time compared with RFA and, as such, has largely replaced RFA as the preferred thermal ablation modality at many institutions. Unfortunately, however, there are limited data on the immunologic ramifications of MWA and, as discussed previously, it cannot be assumed that RFA and MWA are interchangeable from an immunologic perspective.Studies investigating the immune response following MWA report an increase in circulating immune cells and pro-inflammatory cytokines. In a clinical study of 89 patients, Dong et al.  reviewedData on the influence of MWA protocol parameters on the immune response are limited. The aforementioned study by Yu et al.  comparedThere is preclinical and clinical evidence to support the use of MWA combined with immunotherapy. Jing et al. reported two preclinical studies in mice with hepatic tumors evaluating dendritic cell immunotherapy in combination with MWA. The first study  includedHigh intensity focused ultrasound (HIFU) differentiates itself from other hyperthermia modalities by the fact that it is completely non-invasive. Furthermore, in addition to hyperthermia, HIFU can also generate non-thermal mechanical damage within the tissue through a phenomenon known as acoustic cavitation. From an immunologic perspective, this mechanism of action should be very effective at releasing DAMPs and this hypothesis has been borne out in both clinical and preclinical studies.Numerous studies suggest that HIFU causes ICD in cancer cells and the subsequent release of danger signals including HSP-27, HSP-60, HSP-70, HSP-72, HSP-73, tumor-associated antigens and ATP ,77,78,79Indeed, subsequent studies showed evidence of HIFU-induced immunological anti-tumor effects such as an increased immune cell infiltration and the ability of tumor debris to activate immune cells. The aforementioned study by Hu et al.  found thStrategies to optimize the delivery of thermal FUS and its immunostimulatory effects have been pursued. A study by Liu et al.  investigIl6 and Il1β, which the authors hypothesized could promote a chronic inflammatory pro-tumor environment, was attenuated and the tumor infiltration by dendritic cells was enhanced with the addition of immunotherapy. Taken together, these findings suggest that HIFU primed with immunotherapy may elicit a more robust, global and lasting anti-tumor adaptive immune response compared with either monotherapy.It is hypothesized that HIFU-induced ablation alone is insufficient to cause a lasting immune response against the tumor particularly those prone to a recurrence or metastasis in part because the resultant coagulative necrosis dampens the immunostimulatory response . ContempThe clinical unmet need for an adjuvant intervention to boost the efficacy of systemic immunotherapies coupled with the immunologic impact of ablation has led to the recent activation of numerous combination clinical trials .These trials will provide crucial advances in our knowledge of both the barriers to immunotherapy and the efficacy of ablation to overcome them. They will also help to address key questions that remain unanswered including such fundamental questions as (1) which modality is the most effective from an immunologic perspective, (2) how should ablation and immunotherapy be sequenced and (3) what are the ideal properties of target lesions or lesions that should be treated with ablation?In one light, the diversity of thermal ablation modalities and procedural techniques is a boon for immuno-oncologists as a great range of variables can be adjusted to identify synergies with systemic immunotherapies. From a practical perspective, however, it is unrealistic to perform optimizations of these parameters in a clinical trial setting and so it is possible that clinical trials may be unsuccessful not because of a fundamental flaw in the rationale for combining hyperthermia with immunotherapy but because of assumptions that had to be made for the sake of expediency in the study design. Such challenges can be overcome by a rigorous investigation of the mechanistic framework underpinning the immunologic ramifications of hyperthermia in the preclinical setting. While most prior preclinical studies have focused on the effects of hyperthermia , few have delved deeper into the underlying mechanisms. An appreciation for the cellular and molecular perturbations caused by hyperthermia on the tumor microenvironment will be invaluable in designing strategies to maximize the immune effects of hyperthermia.There is a substantial unmet need for adjuvant interventions to augment the efficacy of a systemic immune checkpoint inhibitor therapy. Numerous barriers to immunotherapies exist including the elaboration of immunosuppressive cytokines, immunosuppressive myeloid cells within the tumor microenvironment and a lack of exposure of tumor antigens to APCs. Hyperthermia modalities have demonstrated significant promise for addressing these barriers in preclinical models and multiple ongoing clinical trials will evaluate their efficacy in patients. As our mechanistic understanding of the immunologic ramifications for these interventions grows, we will be able to tailor our approaches in a patient-specific manner.


The global population is projected to increase to near 10 billion people by the year 2050 —some autThe sustainable intensification of agricultural production is needed to meet food demand while maintaining functioning and healthy ecosystems. Currently, biotechnological tools are being used to complement conventional crop management; among them, the use of bio-products containing beneficial microorganisms, also known as microbial inoculants or bioinoculants, is gaining importance in this matter . FortuneThe integration of beneficial microorganism–plant interactions into crop production programs represents a promising sustainable solution to improve agricultural production. However, the success of bioinoculants applied in the field is highly determined by the scientific research and agro-biotechnological innovations behind them. Therefore, the study of and research focused on understanding the complex interactions between beneficial microorganisms, plants, and their environment, as well as the bioprospecting needed to massively exploit these interactions, are crucial to moving knowledge from labs to fields as commercial effective products.As its Guest Editors, we are confident that this Special Issue will collect and inspire high-impact research activities, offering new insights into wide-ranging topics and approaches to the role of often-unexploited microbiota in agriculture for providing sustainable alternatives to warrant global food security.


Genetically modified food animals (GMFAs) are needed to address early the cumulative effects of livestock production on the environment, and to accommodate future food demands. In 2020 China and the USA, the world's two largest economies, embarked on regulatory reforms to boost the commercialization of such animals. However, gaining social acceptance of GMFAs for commercialization remains a global challenge. We propose a framework that focuses on social license for commercialization of GMFAs by defining four classes of improvement using precision genetics: (1) animals equivalent to natural variation to obtain the improved effect of cross-breeding (ENV); (2) animals with an inactivated gene that could occur via natural mutation (ENC−); (3) animals harboring a natural genetic sequence isolated from another species (ENC+); and (4) animals with synthetic sequences encoding novel genes (BNE). Our approach can guide regulators and the public to support orderly commercialization of GMFAs. TM pigs, the first-of-its-kind intentional genomic alteration in GM livestock for medical and/or food use [Since late 2020, China and the United States, the world's two largest economies, have embarked on regulatory reforms to boost the regulatory development of genetically modified food animals (GMFAs). The Ministry of Agriculture and Rural Affairs of the People's Republic of China issued a circular to encourage original innovation of agriculturally important, genetically modified organisms (GMOs) as well as to standardize and regulate the transport, transfer and cross-breeding of biological materials . The US food use .Public concerns about GMFAs reflecting a lack of social acceptability have been obstructing regulatory approval of GMOs for commercialization in both countries. In China, except for papaya and cotton (cottonseed oil), no GM plant or animal has been entered into commercial cultivation and breeding for food . In the With the advent of genome editing, precise genetic changes in GMFAs can be achieved and incorporated into selective breeding programs. However, applying transformational genetics requires social license, a concept based on ethics, history, customs, etc., which are difficult to apply to scientific technologies that are evaluated in quantifiable terms. Science can define the characteristics of a GMFA but cannot answer public policy questions about whether it should be commercialized. Here, we propose a strategy to evaluate GMFAs for safety and commercialization and thereby encourage broader international support of GM agriculture.Most industrialized countries support animal research that meets international ethical guidelines. Social evaluation for commercialization is based on the animal's attributes in terms of benefit to humans, to themselves, and to the environment, that is to help fulfill societal needs. A common social concern has been that GMFAs are unnatural, which makes them wrong. The concept of naturalistic fallacy of inferring evaluative conclusions from purely factual premises is relevant to this public perception. We propose evaluating GMFAs in terms of their natural equivalence to traditional breeding, with the understanding that GM technology can obtain a desirable genotype within a single generation. Ranking genomic alterations in GMFAs compared to present-day food animals is a method that can be intuitively understood by the public. There is precedence for this approach. In 1993, the Organization for Economic Cooperation and Development (OECD) proposed the Principle of Substantial Equivalence (SE), which states that a new food or food product should be considered equally safe to an existing food or food product if it contains essentially the same ingredients. However, this approach may defeat the whole idea of using GM technology to make desired improvements in livestock beyond those which could occur incrementally in nature. Adoption of a GM food should be evaluated by the need(s) it can safely fulfill.Accordingly, we propose expanding the concept of SE by distinguishing four classes of GMFAs. (1) Equivalent to natural variation (ENV) achieved through GE that introduces a beneficial genetic sequence that already exists in a subpopulation of the same species to obtain the improved effect equivalent to natural crossbreeding (ENC). That is, if there are natural mutations that can mimic the changes made in ENV GMFAs, then these animals should be acceptable by a majority of the informed public. (2) ENC−, a species in which an endogenous gene is inactivated (knock-out); gene inactivation is a natural process that can be achieved efficiently using genome editing. (3) ENC+, insertion of a new genetic sequence (knock-in). ENC+ includes GMO-type changes for which the effective phenotype is predictable; currently most ENC+ GMFAs will employ site-specific insertions of the new genetic sequences to avoid questions of unknown effects from random integration. (4) Beyond Natural Equivalence (BNE), GMFAs with synthetic sequences encoding novel genes. BNE traits may derive from the introduction of novel biochemical pathways to improve the animal's productivity and/or environmental friendliness.MSTN) that leads to both increased skeletal muscle mass and improved taste [C. elegans Fat1 gene [Given the successes of traditional breeding, obtaining social license and public acceptance for commercialization, the regulatory oversight for ENV and the ENC− GMFAs should be no greater than for conventional agricultural animals that result from cross-breeding to introduce superior traits into particular breeds otherwise adapted to specific regions or agricultural practices. Likewise, the evaluation process of ENC+ animals needs to be simplified on the basis of the existing GM regulatory system that has been in place for many years. ENC examples involving animal welfare include natural dehorning in dairy cattle by introgression of the polled sequence variation found in Angus beef cattle  and intred taste . An examat1 gene . Additioat1 gene . Edits oIn 2019, 135 million people in 55 countries experienced severe food insecurity leaving 75 million children with stunted growth and 17 million who experienced wasting. The COVID-19 pandemic is predicted to double these numbers in 2020 . Social Economic considerations are vitally important to granting social license to GMFAs. Economics has always been the driving force for agricultural advancements. Sponsors of a GMFA need assurance that consumers and regulatory agencies will be receptive to the new product. The terrible specter of future food insecurity and attendant societal disruption is presently of little concern to most people in most societies. Given food shortages in coming decades, serious thinking about the commercialization of GMFAs today could ensure that BNE GMFAs will be developed by researchers and fully characterized for integration into nucleus breeding herds for when they are needed. Our collective current thinking must extend beyond the present to directly consider the future needs of everyone on our planet, which is experiencing rapidly changing climates. Staged introduction of GMFAs will be a vital contribution to future food security.


Mobile Health  interventions have received a mix of praise and excitement, as well as caution and even opposition over recent decades. While the rapid adoption of mHealth solutions due to the COVID-19 pandemic has weakened resistance to integrating these digital approaches into practice and generated renewed interest, the increased reliance on mHealth signals a need for optimizing development and implementation. Despite an historically innovation-resistant medical ethos, mHealth is becoming a normalized supplement to clinical practice, highlighting increased demand. Reaching the full potential of mHealth requires new thinking and investment. The current challenge to broaden mHealth adoption and to ensure equity in access may be overcoming a “design purgatory,” where innovation fails to connect to practice. We recommend leveraging the opportunity presented by the COVID-19 pandemic to disrupt routine practice and with a new focus on theory-driven replicability of mHealth tools and strategies aimed at medical education and professional organizations. Digital health technologies have fundamentally transformed the way we interact with each other, access health information, and seek care. As an example, during the COVID-19 pandemic, mHealth technologies have shown their effectiveness in supporting usual services disrupted due to the pandemic and restrictions on in-person care. Further, mHealth has been helpful in monitoring atrial fibrillation, predicting COVID-19 symptom progression, and identifying need for ventilation  and downstream (design) insights to further the promise of mHealth. Moving from theory to practice, mHealth requires the intentional engagement of patients, clinicians, health system administrators, and leaders in medicine to think beyond traditional perspectives that may resist change. It requires digital health proponents and critics to recognize that technology can only improve care by moving toward replicability, reaching vulnerable patient groups who stand to benefit most from improved access to quality and timely care, and novel approaches to ensure sustained adoption and delivery of these digital platforms in routine care settings. This ensures mHealth’s future as a respectable and appropriate care delivery solution and not as an ad hoc supplement to existing medical care.


The cost of raising grandchildren on grandmothers’ mental and physical health has been well-documented; however, little is known about whether raising grandchildren also has a cost on grandmothers’ relationships with the adult children whose children the grandmothers have raised. Drawing from theories of exchange and affect, stress process model, and racial differences in intergenerational solidarity, we tested how raising grandchildren affects grandmother-adult child relations. Further, we explored the extent to which these patterns differed by race. To address this question, we used mixed-methods data collected from 553 older mothers regarding their relationships with their 2,016 adult children; approximately 10% of the mothers had raised one or more of their grandchildren “as their own.” Data were provided by the Within-Family Differences Study-I. Multilevel analyses showed that raising grandchildren was associated with greater closeness in grandmother-adult child relationship in Black families; however, in White families, raising grandchildren was associated with greater conflict in the grandmother-adult child relationship. Further, the differences by race in the effects of raising grandchildren on closeness and conflict were statistically significant. Qualitative analyses revealed that race differences in the association between raising grandchildren and relationship quality could be explained by mothers’ reports of greater family solidarity in Black than White families. Our findings highlight the ways in which race and family solidarity interact to produce differences in the impact of raising grandchildren on Black and White mothers’ assessment of the quality of their relationships with their adult children, consistent with broader patterns of racial differences in intergenerational cohesion.


Standardization and harmonization of healthcare resource utilization data can improve evaluations of the economic impact of treating people with substance use disorder (SUD), including reductions in use of expensive hospital and emergency department (ED) services, and can ensure consistency with current cost-effectiveness and cost-benefit analysis guidelines.We examined self-reported healthcare and other resource utilization data collected at baseline from three National Institute on Drug Abuse (NIDA)-funded Seek, Test, Treat, and Retain intervention studies of individuals living with/at risk for HIV with SUD. Costs were calculated by multiplying mean healthcare resource utilization measures by monetary conversion factors reflecting cost per unit of care. We normalized baseline recall timeframes to past 30 days and evaluated for missing data.We identified measures that are feasible and appropriate for estimating healthcare sector costs including ED visits, inpatient hospital and residential facility stays, and outpatient encounters. We also identified two self-reported measures to inform societal costs . Missingness was 8% or less for all study measures and was lower for single questions measuring utilization in a recall period.We recommend including measures representing units of service with specific recall periods , and collecting healthcare resource utilization data using single-question measures to reduce missingness.The online version contains supplementary material available at 10.1186/s13011-021-00356-z. Economic evaluation is a critical tool to determine the value of substance use disorder (SUD) treatment. A 2017 report from the Council of Economic Advisors to the President highlighted the need for economic analyses to evaluate and improve the delivery of SUD treatment in the United States (U.S.) . When saAn economic evaluation examines the cost of a prevention or treatment intervention, program, or policy in the context of potential downstream cost-offsets. These analyses leverage data across healthcare and non-healthcare domains . NationaData harmonization in research pertaining to SUD, HIV, hepatitis C virus (HCV), and other related diseases and disorders is a high priority research area for the National Institute on Drug Abuse (NIDA) . NIDA fuTo gain access to individual-level, de-identified STTR study data, we submitted a concept proposal to the STTR Data Coordination Center at the University of Washington, which was reviewed and approved in 2016. Individuals interested in collaborating or working with these data should contact the STTR Data Coordination Center at sttr@uw.edu. For this study, we initially selected six STTR studies based on similarity across baseline questionnaires and relative completeness of de-identified baseline data. Three of these studies were later excluded because the baseline questionnaires collected healthcare resource utilization data without specific recall periods and could not be used to meaningfully calculate costs.Collectively, 868 people living with HIV with or at high-risk for SUD are represented in three studies: (1) PACTo: Enhanced Access to HIV Care for Drug Users in San Juan, Puerto Rico, which implemented and evaluated a community-level, structured approach to 409 people living with HIV who use substances in five communities in San Juan from 2014 to 2017 ; (2) ProWe identified healthcare resource utilization measures common to at least two of the selected studies with comparable recall periods, and categorized them into three domains: general medical care , SUD treatment ), and medications  Table . We alsoWe reviewed common healthcare resource utilization measures to identify outcomes that are comparable across studies and could potentially be used for economic analyses. A prerequisite was that variables must represent units  over a specific recall period . Dichotomous measures such as “ever been treated for substance use disorder” or measures over lifetime cannot be meaningfully monetized for use in economic evaluations. We identified 10 measures that met this criteria and were representative of the healthcare sector perspective. These measures captured data on ED, inpatient hospital and residential facility, and outpatient encounters. Additional measures informed a broader, societal perspective by capturing reported number of days experiencing alcohol- or drug-related problems, and participant spending on alcohol or drugs in a given recall period. Some of these measures evaluated utilization during a specified time frame using response from a single question  whereas other measures captured utilization using a combination of questions  to calculate the total number of hospital days in the recall period.We constructed descriptive statistics for each measure across all three studies Table . To normor if one of the two questions was answered with a positive response and the other with a zero , we considered the response to that measure to be missing due to incompatability of combined responses. Invalid compound missingness was only applicable to the combined measures of utilization, whereas missingness due to absence of information or out-of-range responses was applicable to all measures. For the purpose of this study, which was limited to baseline data, we removed missing responses to individual measures from our analysis through case deletion, rather than create a complete data set through imputation.Missingness was low across the three studies. We categorized missing data as: 1) an absence of information or 2) invalid responses . In our As dictated by the healthcare sector and societal perspectives, we attempted to find MCFs designed to capture the value of the resources utilized, without accounting for other characterstics, such as profit . We usedThis study does not represent direct human subjects research and was a secondary analysis of de-identified data from STTR studies; each original study had IRB approval. This study was completed under a data sharing agreement with the STTR Data Coordination Center in which all authors agreed to respect and protect the privacy of the original participants.Baseline healthcare resource utilization represented by varying timeframes ranging from 30 days to lifetime is presented in Table We calculated means and standard deviations for baseline healthcare resource utilization, per 30-day period, across the three studies Table . From thAverage baseline healthcare resource utilization costs are reported in Table Given these data were taken from baseline assessments, responsiveness and completeness of data were generally high and loss to follow-up was not applicable. Rates and causes of missingness across the three studies is captured in Fig. The primary objectives of this study were to review commonly collected healthcare resource utilization measures from three studies, and propose standards that would allow enhanced comparability across studies; and to report standardized healthcare resource utilization cost estimates according to different stakeholder perspectives. We identified common healthcare resource utilization measures across the three studies, all of which were reported for the past 6 or 12 months. Questions asked over a lifetime timeframe were excluded because they could not be monetized meaningfully – a discrete measure of frequency and duration is necessary in order to enumerate costs. Only one common measure  was asked as a single question. Other measures required additional effort in order to combine responses into a measure of units of service over a specific recall period. These combined frequency/duration measures of healthcare resource utilization resulted in an increased opportunity for invalid compound missingness.Self-report is a common means of comprehensively capturing healthcare resource utilization in the absence of data from a fully integrated healthcare system or insurance claims, and has been shown to be reliable when compared to administrative and medical claims data, particularly over shorter recall periods; extrapolating these results in order to infer costs over longer timeframes is inexact and subject to recall bias , 29, 30.In addition to harmonization of recall timeframes, we recommend the use of single-question measures in order to minimize missingness due to incompatible compound responses. For instance, responses to the question “In the last 30 days, how many days did you spend in a residential drug or alcohol treatment facility or detox hospital?” are immediately quantifiable, as they represent a count of service utilization over a specified timeframe. While we employed case deletion for the purposes of this study, best practice is to assess the mechanism of missing data (e.g. missing at random) and employ a relevant and robust method for controlling for missing data bias  .These findings are meant to support ongoing data harmonization efforts in the fields of SUD, HCV, and HIV research. Helping to End Addiction Long-term (HEAL) Initiative funding opportunities supported by NIDA in response to the opioid crisis include integrated studies to develop, test, and validate evidence-based approaches to preventing and reducing opioid use disorders, overdoses, and overdose fatalities . InvestiDeveloping a common set of tools and resources for assessing utilization of healthcare resources, as well as other relevant measures such as criminal activity , will prHarmonizing and standardizing data measures allows for more accurate comparisons of outcomes across studies, as well as cross-study analyses. We recommend using single question measures representing units of service with specific recall periods in order to minimize missingness and generate responses that can be enumerated using standard MCFs consistent with current cost-effectiveness and cost-benefit analysis guidelines. These results can be used in cost-effectiveness and cost-benefit analyses to estimate the relative economic value of reducing healthcare resource utilization through effective interventions. Identifying the downstream economic impact of one SUD treatment or prevention strategy relative to another greatly enhances the ability of stakeholders to invest scarce resources in a manner that will allow them to reach the greatest number of those in need.Additional file 1: Figure 1. Causes of Missing Data Across Three STTR Studies.


There is a lack of high-quality evidence underpinning many contemporary clinical practice guidelines embedded in the healthcare systems, leading to treatment uncertainty and practice variation in most medical disciplines. Comparative effectiveness trials (CETs) represent a diverse range of research that focuses on optimising health outcomes by comparing currently approved interventions to generate high-quality evidence to inform decision makers. Yet, despite their ability to produce real-world evidence that addresses the key priorities of patients and health systems, many implementation challenges exist within the healthcare environment.This manuscript aims to highlight common barriers to conducting CETs and describes potential solutions to normalise their conduct as part of a learning healthcare system. Many recommendations contained in contemporary clinical practice guidelines (CPG) are not supported by high quality evidence . In AustComparative effectiveness trials (CETs) address this conundrum by randomising participants to usual care alternatives in order to generate unbiased, high-quality evidence of the relative effectiveness of existing treatments . Their pAs the treatment options investigated are widely used in practice, the additional risk to patients is low. Furthermore, public opinion polls repeatedly confirm that patients want their health systems to be ‘research active’ so that they are better informed about the benefits and risks of different treatments –6. It seMany factors have stymied attempts to integrate CETs into clinical care. Indeed, the characteristics that support their pragmatism can also hamper their conduct. For example, to preserve external validity, CETs necessarily avoid certain design features required for high internal validity,  . HoweverHealth system leaders too are reluctant to allocate resources to support trial activity, perhaps because the research agenda has historically been driven by academics and the trials conducted within their institutions have not always been in line with health system priorities.One of the most significant barriers to the adoption of CETs for contemporary evidence generation is the absence of proportionate approaches to trial governance.Currently, the policy framework and governance arrangements applied to CETs are largely identical to those for trials involving novel interventions. For example, some CETs compare interventions in which verbal consent to treatment would have been obtained outside the trial setting. Yet, when formally comparing two standard treatments, lengthy, legalistic consent forms are mandated, despite growing evidence that patients prefer simpler ways to be informed about such research that do not overinflate the perception of risk , 11. TheEfforts to develop, design and conduct CETs will continue to require creative approaches to overcome common challenges. Table The failure of health systems to ground everyday treatments in sound science impacts the quality of care provided to patients and contributes to health system waste. Conducting CETs that provide robust and generalisable evidence to guide practice is a public good. Importantly, patients recognise this and consistently confirm that they want their health systems to be research-active.Although some progress has been made, few healthcare organisations have successfully transitioned into LHSs that conduct trials as an integral part of the delivery of high-quality care. Despite progress in areas such as trial design, lingering challenges remain, not least, the need to develop risk-proportionate regulatory and governance frameworks that facilitate the conduct of large, pragmatic CET by them being less expensive and cumbersome to conduct.Implementing solutions that address the factors that currently prevent the embedding of CETs as a core activity of the health system will require disruptive change, but without such change, the widespread use of low-value or suboptimal treatments will remain unchecked.