Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation. The development and progression of cancer involves a growing compilation of genetic and epigenetic alterations which affect cellular function and impart qualities that promote self-sufficiency, survival and motility. Influencing these transformations is an ever-changing metabolic milieu that affects cancer cell behavior, and in turn, is influenced by growth of the cancer itself. Transient periods of hypoxia and nutrient deprivation interplay with production of angiogenic factors and alterations to cellular metabolism. As this progression continues, genetic instability drives metabolic adaptations that promote utilization of available substrates in suboptimal growth conditions. Importantly, changes to cellular metabolism are orchestrated by signaling pathways that increase aggressive behaviors and mediate resistance to therapies. Pioneering work in the field has led to profound insight on how metabolic adaptations drive phenotypic qualities that foster the development of metastatic traits ,2.The early work of Warburg focused attention on glucose and the ability of cancer cells to maintain robust anaerobic metabolism, even in the presence of available oxygen, a concept that became known as aerobic glycolysis, or the Warburg effect . KeepingIt is established, however, that not all cancer metabolism is centered on glucose, and while mitochondrial dysfunction can occur, these unique cellular organelles within cancer cells are not defective as had been proposed long ago. Indeed, many reports have characterized cancer cells with high oxidative mitochondrial metabolism ,17,18,19Despite this adaptability, the availability of glucose during tumor growth undeniably affects metabolism. Of equal magnitude is the influence exerted by its absence. The ability of cells to reprogram, or switch to and from glycolytic metabolism, relates to a phenomenon described in yeast known as the Crabtree effect where high glycolysis rates actively, and reversibly, inhibit components of mitochondrial metabolism . AlthougThroughout these changes, cancer cells are effective at communicating with each other, with stromal cells of the primary tumor tissue, those of secondary sites, and cells encountered during the metastatic cascade . Thus, cWhat we know about connexins and their functions in cancer has been exceedingly expanded by the field over the last half-century . MechaniConnexins were originally described as the proteins responsible for the formation of cell–cell membrane channels that allowed for direct exchange of small molecules between cells ,40. In hStructurally, connexin proteins consists of four hydrophobic transmembrane domains, two extracellular loops, one cytoplasmic loop and intracellular N- and C-terminal domains A. The le+ and ions through hemichannels contribute to physiologic processes including purinergic signaling, Ca2+ regulation and apoptosis , contributing to extracellular acidification of tumor microenvironments. This acidification can eventually dissipate the intracellular/extracellular H+ gradient. Furthermore, cells within the core of a solid tumor have limited exposure to the surrounding environment and blood supply, reducing the opportunity for metabolic exchange. This creates a challenge for cancer cells to export metabolites such as lactate and maintain proper intracellular pH.Due to the ability of gap junctions and hemichannels to allow for transport of small molecules, including glucose, a natural capability to couple metabolism between cells has been established in this regard ,154,155.3−) from oxygenated peripheral cells to spheroid cores [+, this creates a favorable gradient for HCO3− diffusion into the spheroid, coupling and normalizing intracellular pH. Knockdown of Cx43 ameliorated the cell–cell effects in each case. These reports demonstrate a distinctive mechanism of GJIC to promote substrate channeling between cancer cells, alleviating metabolic inhibition and supporting tumor growth. The uniqueness of such a coupling system in the absence of a blood supply, is the fact that gap junctions are the primary mechanism for direct cell–cell exchange of molecules. This underscores the appeal for cancer cells to utilize connexins as a means of molecular networking, contributing to higher-order coordinated function at the multi-cellular level of a tumor. When loss of GJIC is observed in primary tumors, this may therefore relate to differences in vasculature perfusion and changing metabolic pressures.Work in pancreatic ductal adenocarcinoma cells using three-dimensional growth assays demonstrated that Cx43 gap junction channels facilitate the exchange of lactate directly between cells of growing spheroids by transferring it away from the inner core . This ocid cores . Taken tA study taking a similar approach in colon cancer cells evaluated the roles of GJIC on nutrient facilitation in three-dimensional colon cancer tumor spheroids. Results from this study showed the ability of Cx43 to mediate transfer of glucose from the periphery to the core . This coCoupling of metabolites also occurs between cancer cells and stromal cells. In a process known as the reverse Warburg effect, cancer cells induce high rates of glycolytic metabolism in surrounding stromal cells, which then produce metabolites such as pyruvate and lactate that are used by the cancer cells, which take on an oxidative metabolism for efficient ATP production ,160. ThiStudies such as these demonstrate that cancer cells are capable of coupling not only their own metabolism, but co-opting the metabolism of other cells to fuel their demands through the use of GJIC. This allows for accessibility to glucose and venting of intermediates in the absence of blood perfusion. These processes have significant implications on the establishment of metastatic adaptation when cells extravasate to secondary sites and must adapt to new microenvironments.266-283) that reproduces the binding and inhibition of c-Src by full length Cx43, this inhibition was shown to affect GSC qualities [266-283 decreased glucose uptake by reducing hexokinase activity. Moreover, this inhibition reduced the ability of GSCs to adapt to different nutrient limitations. When GSCs were grown in media containing glucose and lacking amino acids, cells adapted by increasing expression of glucose metabolizing enzymes hexokinase-II (HK2) and glucose-6-phosphate dehydrogenase (G6PD), while decreased levels of these enzymes, along with GLUT3 (SLC2A3), a glucose transporter highly expressed in the nervous system, were decreased in TAT-Cx43266-283 treated cells. The response involving decreased hexokinase-II and GLUT3 was also recapitulated using an orthotopic murine model of glioblastoma. The results indicate potential tumor suppressive roles of Cx43 related to its ability to block adaptation to glucose utilization through inhibition of c-Src. This effect is likely to be context specific between cancers and dependent on c-Src status.Among the many protein interactions of the Cx43 C-terminal tail is c-Src (SRC), a non-receptor tyrosine kinase and proto-oncogene which phosphorylates Cx43 and decreases GJIC ,165,166.ualities . HexokinStudies using C6 rat glioma cells have placed an additional focus on hexokinase and gap junction regulation. Hexokinase enzymes can be tethered to the mitochondrial membrane which increases activity, provides a source of ATP and reduces degradation. This mitochondrial association is also a feature of cancer cells, and can contribute to higher glycolytic rates. Increasing GJIC in the C6 cell line with tolbutamide or dbcAMP (which promote GJIC through mechanisms that include increased connexin expression and improved connexin trafficking to the plasma membrane), led to dislocation of both hexokinase I (HK1) and II from the mitochondria to the cytosol . This alImportant questions exist regarding metabolic substrate switching based on nutrient availability and the function of connexins, gap junctions and hemichannels. A wealth of reports have described the effects of glucose availability and metabolic inhibition on connexin expression and function through experimental models in the context of diabetes and its complications such as diabetic retinopathy and nephropathy. Many of these studies have demonstrated an effect of downregulation on connexin expression and/or gap junction activity in response to high glucose levels ,202,203.In a study bridging these areas, Cx45 (GJC1) was implicated in a potential connection between liver cancer and diabetes . The basThis later finding is intriguing as O-GlcNAcylation, which involves the posttranslational addition of N-acetylglucosamine (GlcNAc) to affect protein stability and localization, has received much attention for its significant connections to glycolysis and metabolic reprogramming in cancer cells ,220,221.A study from a different perspective evaluated the effects of reduced glucose availability on metastatic breast cancer cells. Using the MDA-MB-231 triple-negative breast cancer cell line, long-term glucose limitations induced the emergence of an adapted population with altered morphology and a significantly increased invasive capacity through Matrigel . These cCollectively, these studies demonstrate the ability of GJIC to couple tumor cells metabolically and promote growth within hypoxic regions. They have also shown how connexin functions alter activity of glycoysis and glucose uptake. Importantly, they provide evidence for the promotion of cancer cell qualities in context-dependent responses to high or low glucose, confirming a mutual relationship between the function of connexins and availability of glucose .2+ transfer between the ER and mitochondria [Changes to the synthesis and processing of connexins in cancer cells may play a role in cancer cell metabolic adaptations. The endoplasmic reticulum associated degradation (ERAD) pathway targets misfolded or damaged proteins within the ER and transports these proteins for ubiquitination and processing by the proteasome. ERAD contributes to turnover of connexins, especially in cells with high expression, or in experimental models involving overexpression ,227. Furchondria ,234,235.Glucose availability has clear implications on the process of autophagy, and since connexin proteins are both targets and regulators of this pathway, consideration must be given to how this affects connexin dynamics in cancer cells ,237,238.Cx43 is found within the inner mitochondrial membrane and while much of the functional relevance regarding this localization is unclear, its role has been implicated in complex conditions including cardiac ischemia/reperfusion injury and cell death ,242,243.The phosphatidyl-inositol 3 kinase (PI3K) pathway induces a signaling program that supports cellular growth and survival, and its activity is highly implicated in cancer. Downstream of growth factor binding, PI3K leads to activation of AKT serine/threonine kinases (ATK(1-3)) that phosphorylate numerous targets, collectively promoting cellular survival, energy metabolism and growth ,247. AmoConversely, connexins are also regulated by nutrient sensing pathways during times of reduced cellular energy availability. AMPK is stimulated when ATP levels decrease and works to inhibit biosynthetic processes while adjusting cellular metabolism based on substrate availability . Connexi266-283 [Limitations to nutrients such as glucose due to a lack of sufficient blood supply are inherently coupled with hypoxia. Therefore, the study of nutrient limitation effects on cancer cell qualities must be taken into consideration with changing states of oxygen perfusion. HIF1α (HIF1A) is a known response element activated during times of decreased oxygen availability and is highly regulated at the protein level, responding to hypoxia through transcriptional regulation of genes that affect metabolism, and is interconnected with PI3K signaling and cancer ,269,270.266-283 . These r266-283 . Recentl266-283 . Using bAn area that will surely provide significant insight to connexins and energy metabolism, is exploration of the numerous transcriptional programs controlled by glucose. Studies such as those by Chen et al. discussed above, are important for connecting connexin gene regulation to substrate metabolism . AdditioOf the numerous specific transcription factors that regulate connexin expression, many are influenced by nutrient accessibility. For example, Iroquois homeobox gene 3 (IRX3) has divergent roles on connexin expression, suppressing Cx43 while upregulating Cx40 in cardiac cells . More reAdding to the regulation of connexins at the mRNA level, a growing number of miRNAs have been reported to affect glucose metabolism and an expanding list of connexin transcripts are regulated by miRNAs ,301,302.Perhaps one of the most interesting growing areas linking cancer metabolism and connexin regulation involves the role of short-range communication mechanisms. Extracellular vesicles are lipid-bilayer bound particles released from cells and include exosomes which range in size from 30 to 200 nm and originate from endocytic machinery, and microvesicles, which are larger (approximately 100–1000 nm) and result from budding of the plasma membrane . These eAnother area receiving attention in the field of cancer metabolism is the role of tunneling nanotubes (TNTs). These thin projections of the plasma membrane are capable of connecting cells over long distances to allow for direct exchange of molecules ,324,325.Because glucose and the pathways that control its utilization are central to cellular metabolism and interconnected to a multitude of signaling pathways, it is not difficult to find connections between connexin function and glucose metabolism. However, clearly defining the roles, mechanisms and dependencies of this relationship remains a formidable task of cell biology and biochemical analysis, especially within the context of cancer. The constantly shifting metabolism of tumor cells and their fluctuating microenvironment coupled with genetic changes that alter nutrient consumption, present challenges when attempting to recapitulate this indeterminate setting experimentally.Standard cell culture conditions typically utilize supraphysiological concentrations of nutrients, oxygen pressures and an environment of static versus perfused substrate metabolism without stromal influence or tissue structure. Nonetheless, studying connexin dynamics in a metabolically sequential, albeit controlled environment remains important, while utilization of more advanced culture techniques and metabolomics approaches will be imperative to fine tune what we know about these developing relationships ,328,329.It is clear that connexins play multiple roles in controlling glucose (and cellular) metabolism while responding to environmental and intracellular nutrient sensing. More roles will be described as attention to this area continues to increase. Importantly, the growth of knowledge regarding these associations will shed light on clinical and therapeutic implications.


Objectives: To synthesize the current available evidence on the changes in food intake and food selection after physical relocation in non-refugee populations.Methods: The inclusion criteria were studies with a measurement of food selection and/or food intake in non-refugee populations where physical relocation had occurred with self-reported or objective assessment of the neighbourhood physical environment before and after relocation. Databases searched included MEDLINE, EMBASE, CINAHL and SCOPUS from 1946 to August 2022.Results: A total of four articles met the inclusion criteria. Overall, these studies gave longitudinal (n = 2) and cross-sectional (n = 2) evidence to suggest that moving to an urban neighbourhood with more convenience stores, cafés and restaurants around the home was associated with an increase in unhealthy food intake in adult populations. Additional factors such as income, vehicle access, cost, availability and perceptions of the local food environment played a role in shaping food selection and food intake.Conclusion: Four internal migration studies were found. The limited evidence base calls for more research. Future studies should include children and apply appropriate research designs to account for neighbourhood self-selection and concurrent life events. International migration studies should include assessment of neighbourhood physical environments pre- and post-relocation. Evidence-based elements of a healthy diet include emphasizing fruits and vegetables, unsaturated fats, whole grains, plant protein sources and limiting consumption of trans and saturated fats, highly refined grains and sugary beverages [Unhealthy diets are a significant risk factor for chronic disease, disability and premature death . One of everages . A key heverages . The Woreverages  and the everages  recommeneverages –11. A meeverages . Fruit aIn Sub-Saharan Africa, daily fruit and vegetable intake (268 g) remain below the World Health Organization’s recommendation (400 g) [Available data globally suggests insufficient fruit and vegetable consumption. For instance, a majority of adults in Australia, Canada, the UK, and US do not meet recommended fruit and vegetable consumption guidelines –15. In S (400 g) . Healthc (400 g) –15, 17.  (400 g) , healthcDietary behaviors and food consumption are shaped by interrelated personal and environmental factors, including knowledge , affordaUnderstanding how individuals interact with their physical environment is one crucial component for public health strategies aimed at improving dietary intakes. Previous research usually examines dietary habits and/or neighborhood environment separately, and few studies have dealt with them simultaneously . ResidenTo date, reviews that examined dietary outcomes following physical relocation have generally been limited to mass migrations such as refugee crises –36. ThesA scoping review provides an overview of the literature on a topic and can be most useful when there is a variety of research designs or an expected scarcity of evidence . Guided https://osf.io/3wvfu/) [Our protocol was drafted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) . The fin/3wvfu/) .Searches were conducted from the earliest database inception (1946) to August 2022 in the electronic databases MEDLINE, EMBASE, CINAHL, and SCOPUS for peer-reviewed papers. Search terms included key words related to physical relocation, food selection and food intake see . The detThe focus of this scoping review was available academic literature. Peer-reviewed studies that had any outcome measurement of food selection and/or food intake where physical relocation had occurred (either prospectively or retrospectively) with self-reported or objective assessment of neighbourhood physical environment before and after relocation were included. Non-English publications, gray literature, studies using only refugees or immigrants as the study population, and/or relocation with limited food intake self-selection were excluded. The last exclusion criterion was chosen because eating behaviours within institutional food environments with minimal dietary self-selection may not be comparable to behaviours determined by availability of choices in neighbourhood food environments.Following a standard protocol, potential included studies were screened for eligibility based on the title, abstract and full text. Uncertainty was discussed among all authors and any disagreement was resolved by consensus. A PRISMA flow diagram presents the summary of the study selection process .We did not appraise methodological quality or risk of bias of the included articles, which is consistent with guidance on scoping review conduct . HoweverPublication characteristics, study characteristics and participant information were extracted. Publication characteristics included author, year of publication, publication type, and country in which the study was conducted. Study characteristics included study design, aim and objectives of the study, research methods, neighbourhood environmental attributes (perceived or objectively measured), results and main conclusions. Participant information included number of participants, age and gender. Finally, results regarding sociability and perceived safety were also extracted because both these attributes have also been linked to how the neighbourhood environment could impact residents’ willingness and ability to access nearby food amenities . SociabiThe literature search identified 144 potential studies after removing duplicates. A total of 129 irrelevant documents were removed during phase one screening for the wrong outcomes or incorrect study population. For example, many studies focused on displacement of natural disaster victims or cardiometabolic outcomes. Of the 15 full-text studies assessed for eligibility, four studies met the inclusion criteria and were included in the review –52. The Fruit, vegetable, bread/pasta, milk, meat and refined sugar consumption were the most commonly used food intake outcomes. Grocery stores, home meals and meals consumed outside of the home at convenience stores, cafés and restaurants were the most commonly used locations of food selection. A variety of measures were employed to operationalize these concepts including self-administered questionnaires about usual food intake, lifestyle behaviours, perceptions, self-efficacy, socio-demographic variables and measurements of the neighbourhood environmental attributes.Some studies reported small positive outcomes after relocation , cost and not adjusting habits to favour a healthier diet.Papadaki et al. (2007) reported that lack of experience in planning meals, a general lack of interest in food, or lack of time were also barriers for healthier dietary choices and precipitating factors for increased consumption of take-away and convenience meals.  reportedn = 2) and cross-sectional (n = 2) evidence to suggest that moving to an urban neighbourhood with more convenience stores, cafés and restaurants around the home was associated with an increase in unhealthy food intake. There is evidence that having a greater percentage of healthy food outlets around the home following relocation was significantly associated with an increase in fruit and vegetable intake; however, a majority of participants experienced a decline in the percentage of healthy food outlets around the home following residential relocation compared to a minority who experienced an improvement. Intrapersonal  level characteristics of food intake included preferences/perceptions and knowledge/skills; interpersonal level characteristics of food intake included food availability, social support, time constraints and culture; community/institution level characteristics of food intake included food availability (stores), school/workplace food environment, eating out and access; and policy level characteristics of food intake included food pricing. Biological and psychological determinants of food selection were not tested in these studies. Other economic, physical and social determinants of food selection included cost, income, availability, skills (e.g. cooking), time, culture, family, peers and meal patterns. Furthermore, factors such as vehicle access and availability of public transportation played a role in shaping food selection and food intake, improving outcomes when present.This review found a scarcity of literature on residential relocation and food selection and intake in non-refugee and institutional residential populations that included assessments of food environments pre- and post-relocation, with four publications in four countries (three high-income countries and one lower-income country) meeting the inclusion criteria. The small number of studies and heterogenous designs make it difficult to draw conclusions about associations. Overall, these studies provided longitudinal  and  studies,Findings from these studies generally show less healthy food consumption following relocation. This is consistent with previous literature: a systematic review of 11 studies with university students reported higher salt, fat, and added sugar consumption on campus ; and empThe changes observed in food intakes after relocating are likely also influenced by specific individual factors modifying the way participants respond to a changing environment. For example, having children at home and lower socioeconomic status at baseline were associated with an increase in unhealthy food intake after relocating . Thus, fResidential relocation had some influence on participant behaviour and perceptions. Bvioltsis et al. (2020) found that individual positive perceptions of the local food environment on average decreased from pre-to post-relocation, as indicated by 40.1% of participants reporting a decrease in the presence of a supermarket/grocery store within 15-min walk of home. Previous research has revealed that both objective and perceived measures of increased distance to the nearest supermarket with a good variety of fresh and processed vegetables is associated with decreased daily consumption of fruit and vegetables . Only 5 assessedLimitations inherent to scoping review methodology are that they identify available research and point to research that needs to be conducted on a topic rather than contributing essential research. This review is also limited by restricting studies to English-language publications, exclusion of gray literature, and heterogeneous measurement and outcome measures. Furthermore, no intervention studies were identified. Therefore, only observational studies were available and two of the four were cross-sectional further preventing conclusions about causality.Daily food selection and consumption were estimated through self-reported surveys in all studies, which is subject to measurement error from incorrect recording of food intake and potential reluctance to report consumption of unhealthy foods. For instance, previous literature shows that up to 50% of participants may incorrectly self-report food consumption . There aDespite these limitations, this review has multiple strengths including a comprehensive search strategy to identify available evidence on the topic and avenues for further research. The diversity of the geographical locations provides a representation of the changes in food intake and selection following physical relocation in four different continents compared to earlier reviews on the local food environment that have been limited to studies from primarily higher- or upper-middle-income countries , 71.Residential relocation provides a unique opportunity for studying possible environment-induced changes in food intake and food selection, especially when the environments pre- and post-relocation are assessed. This scoping review identified four studies from three high-income countries and one low-income country: two studies with residential relocation out of the family home to a college campus, one study with residential relocation from a rural to urban environment, and one study with residential relocation from an established neighbourhood to a new residential development. Moving to a new residential development with more convenience stores and restaurants around the home was associated with an increase in unhealthy food intake. Conversely, having a greater percentage of healthy food outlets around the home following relocation was significantly associated with an increase in fruit and vegetable intake; however, a majority of participants experienced a decline in the percentage of healthy food outlets around the home following residential relocation compared to a minority who experienced an improvement. Commonly reported barriers to healthy eating also included lack of time and competing priorities, lack of accessible transportation, no grocery stores within walking distance, cost and not adjusting habits to favour a healthier diet.The limited evidence base calls for more research examining food intake, food selection and residential relocation that include assessments of food environments pre- and post-relocation. None of the studies looked at residential relocation to a different state/province, which may lead to greater changes in the neighbourhood food environment and more significant dietary changes than relocation within the same state/province. None of the studies included children, who may have different dietary preferences and behavioural influences then adults. Future studies could benefit from using longitudinal and interventional designs, such as quasi-experimental studies and cohort studies , evaluat


Moreover, this mediated effect is stronger when subordinates have high interpersonal influence. These findings offer theoretical and practical insights into boundary-spanning activities and leader humor, which we discuss.Based on social information processing theory, we provide a novel theoretical account of how and when leader humor influences subordinate boundary-spanning behavior. We develop a moderated mediation model explicating the mechanism of psychological safety and the boundary condition of subordinate interpersonal influence. Using multiwave data, we tested our research hypotheses with a sample of 452 members from 140 teams in a Chinese information technology (IT) company. Results showed that leader humor positively affects subordinate boundary-spanning behavior  As organizations worldwide increasingly adopt a flatter organizational structure and network-based design, team members are expected to cooperate with both internal and external stakeholders . To do sTraditionally, managing team boundary is the responsibility of formal leaders e.g., . Due to Researchers have demonstrated that leaders play a key role in subordinate boundary-spanning activities . For exaAccordingly, this study aims to answer the above research question through a social information processing theory perspective, which posits that subordinates actively seek to understand and behave according to the norms and expectations in their organizations by processing social information cues . Servingvia psychological safety. Hence, we propose that subordinates with high interpersonal influence are more likely to respond to leader humor and develop psychological safety, which subsequently facilitates boundary-spanning behavior.Notwithstanding the above arguments, the effect of leader humor on subordinate boundary-spanning behavior may vary among subordinates due to their different abilities in sensing the social information cues and calibrating their behavior, as captured by the concept of interpersonal influence . InterpeWe tested our theoretical model by using a sample of 452 subordinates from 140 teams in a Chinese information technology (IT) company, which provided supportive results. Our research makes three main contributions. First, we enrich the theoretical understandings of leadership factors on subordinate boundary-spanning behavior by identifying the role of leader humor. Second, we uncover the mediating role of psychological safety in linking leader humor to subordinate boundary-spanning behavior. Third, we propose subordinate interpersonal influence as a boundary condition that explicates the diverse subordinate responses to leader humor, transferring our insights to consider the question of why leader humor has different effects on subordinate boundary-spanning behavior. Our theoretical model is demonstrated in The use of humor by leaders with their subordinates is receiving growing scholarly interest e.g., . To dateIn this research, we are interested in humor as a behavior rather than sense of humor as a trait , as thisLeader humor reduces hierarchical distance between leaders and subordinates in organizations , which iHypothesis 1. Leader humor is positively related to subordinate psychological safety.Boundary-spanning behavior refers to subordinate efforts to establish relationships with external parties to achieve team tasks and objectives . AlthougCombining the first hypothesis with the above arguments, we propose that psychological safety works as a mechanism that links leader humor and subordinate boundary-spanning behavior. In line with social information processing theory , subordiHypothesis 2. Psychological safety mediates the relationship between leader humor and subordinate boundary-spanning behavior.To understand when leader humor brings more positive consequences, we again follow social information processing theory  and propFrom the social information processing theory perspective, subordinates with different levels of interpersonal influence will attend to the signals that leaders pass on through humor during interpersonal interactions and react accordingly with their own responses . As noteIn stark contrast, subordinates who possess low levels of interpersonal influence are less sensitive to social cues and also less capable of calibrating their behaviors to the situation . When leHypothesis 3. Subordinate interpersonal influence moderates the relationship between leader humor and subordinate psychological safety, such that the relationship is stronger when subordinate interpersonal influence is high.via psychological safety. The strength of this indirect relationship is determined by the level of subordinate interpersonal influence. Specifically, when subordinates have high levels of interpersonal influence, they are more likely to feel psychologically safe through processing the information of leader humor, thereby engaging in more boundary-spanning behavior. Thus, we propose the following hypothesis:Building on the above hypotheses, we further propose a pattern of moderated mediation, in which subordinate interpersonal influence moderates the indirect relationship between leader humor and subordinate boundary-spanning behavior Hypothesis 4: Subordinate interpersonal influence moderates the indirect effect between leader humor and subordinate boundary-spanning behavior via psychological safety, such that the indirect effect is stronger when subordinate interpersonal influence is high.via email and asked them to participate in a voluntary research study involving three stages of data collection with a 2-week time lag. The subordinates were engineers and technicians who worked collaboratively in work teams to set up and maintain IT systems for corporate clients, which made them an appropriate sample for our research. The time lag ensured minimized disruption for the subordinates (on the basis of discussions with management) and allowed the research team to manage the concerns about survey length and common method bias  developed by We measured psychological safety with a seven-item scale developed by We measured boundary-spanning behavior with a six-item scale developed by Following existing studies e.g., , we seleGiven that our data had a nested structure with several subordinates nested in the same teams, it was necessary to address the interdependence issue . We ther2 (164) = 329.28, CFI = 0.95, TLI = 0.94; RMSEA = 0.05; SRMR = 0.05. This four-factor model was significantly better than a three-factor model in which interpersonal influence and leader humor were combined into one factor ; a two-factor model in which interpersonal influence, leader humor, and psychological safety were combined into one factor ; and a single-factor model in which interpersonal influence, leader humor, psychological safety, and boundary-spanning behavior were combined into one factor . The above findings supported the discriminant validity of our research variables.We examined the hypothesized measurement model with four factors  and conducted a series of confirmatory factor analyses to establish the discriminant validity of our measurement model. The fit statistics of the hypothesized four-factor model indicated an acceptable fit: χAlthough we adopted a multiwave design, being faced with the problem of common method bias was still a possibility, we utilized Harman’s single-factor test to examine the possible issue . Based oB = 0.13, p < 0.05), supporting Hypothesis 1. Further, psychological safety was significantly and positively related to subordinate boundary-spanning behavior . We also examined the unstandardized indirect effect coefficients relevant to Hypothesis 2 by using the Monte Carlo simulation to construct the CIs. Based on 5,000 re-samples, the results showed that psychological safety had a significant mediation effect on the relationship between leader humor and subordinate boundary-spanning behavior . Thus, Hypothesis 2 was supported.B = 0.17, p < 0.01). p < 0.01), but insignificant when it was low . Thus, Hypothesis 3 was also supported.As shown in via psychological safety was significantly positive when subordinate interpersonal influence was high , but insignificant when subordinate interpersonal influence was low . Overall, the above empirical evidence supported Hypothesis 4’s prediction that subordinate interpersonal influence moderated the indirect effect of leader humor on subordinate boundary-spanning behavior via psychological safety, such that the indirect effect was stronger when subordinate interpersonal influence was high.Finally, we followed a Monte Carlo-based re-sampling approach to test the model in an integrated fashion. The indirect effect of leader humor on subordinate boundary-spanning behavior via psychological safety is amplified when subordinates have high levels of interpersonal influence. Overall, our research findings extend the literature in several valuable ways and also generate certain practical implications.Based on social information processing theory, our results yield two nuanced insights regarding how and when leader humor drives subordinate boundary-spanning behavior. First, leader humor improves subordinate psychological safety, which in turn increases their engagement in boundary-spanning behavior. Second, the process linking leader humor and subordinate boundary-spanning behavior Our research makes multiple theoretical extensions and has a number of implications for the existing literature. First, our work fills a gap in the literature on boundary-spanning behavior by identifying leader humor as one of the determinants of subordinate boundary-spanning behavior from a social information processing perspective. Given that leaders are of great importance in fostering boundary-spanning activities , consideSecond, our research sheds light on an essential mechanism of psychological safety and integrates the humor literature and boundary-spanning literature at a level of detail that has previously been overlooked in both strands of literature. Scholars have primarily focused on the value of boundary-spanning self-efficacy  and persFinally, our study lends credence to the unique boundary condition of subordinate interpersonal influence, which explains different reactions to leader humor from different subordinates. According to the literature review by Our findings also have the following practical implications. First, our work explores how leader humor stimulates subordinate boundary-spanning behavior, such that when leaders express humor in interactions, subordinates are more likely to have positive responses and engage in boundary-spanning behavior. To this end, we recommend that leaders display humor in social interactions, thereby contributing to positive effects on subordinate psychological state and behavior. Additionally, organizations should strive to integrate humor into leadership training courses  and encoSecond, our research illustrates the mechanism of psychological safety in the relationship between leader humor and subordinate boundary-spanning behavior, which strengthens the argument that subordinate boundary-spanning behavior is driven by the psychological safety established by leader humor. Organizations can thus provide some supportive practices for subordinates to develop and improve their psychological safety, such as mentoring . At the Third, our research shows the moderating role of subordinate interpersonal influence and explicates that subordinates with high interpersonal influence are prone to feel psychological safety and enact boundary-spanning behavior when faced with leader humor. Accordingly, organizations should include interpersonal influence as a selection criterion in the job interview process and provide training programs for subordinates to elevate their awareness of leader behavior . MoreovePrimary among the limitations of this research is our research design. Although we adopted a multiwave design to reduce potential common method bias , this deIn addition, in this research, we have generally conceptualized leader humor as a social behavior  and offeNotably, we captured how leader humor influences subordinate boundary-spanning behavior from a social information processing perspective and uncovered the mediating mechanism of this relationship. Yet we only considered psychological safety as a mediator; there may be other mechanisms  that explain the connection between leader humor and subordinate boundary-spanning behavior. Accordingly, it will be necessary to explore other underlying mechanisms in the future to enrich our current results.Finally, we examined how leader humor can influence subordinate boundary-spanning behavior at the individual level, in line with social information processing theory . HoweverFrom the standpoint of social information processing theory, we theoretically and empirically investigate how and when leader humor sparks subordinate boundary-spanning behavior. Our research results highlight that leader humor plays an important role in stimulating subordinate psychological safety and further boundary-spanning behavior, which is strengthened by subordinate interpersonal influence. We hope that our research provides future directions in the boundary-spanning behavior literature and offers managers practical insights into managing boundary-spanning activities in organizations.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.XW was involved in conceptualizing the research, data analysis, and writing – original manuscript. SL was responsible for the data collection and the manuscript revision. WF was responsible for the theory building, data analysis, and manuscript revision. All authors contributed to the research and approved the submission of this version.


ATP channel agonist, are cardioprotective agents separately but not synergistically.MitoSNO, a mitochondrial-selective S-nitrosating agent, and diazoxide, a K338.See Article page Journal of Thoracic and Cardiovascular Surgery Open, Ahmad and colleaguesIn this issue of the ATP (mito KATP) channels.ATP channels decreases Ca2+ flux from mitochondria and prevents Ca2+-induced myocyte contractility.ATP activation is protective have also been proposed and are being actively studied.It has been shown that MitoSNO provides cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. The S-nitrosation provides protection by limiting the entry of electrons from NADH into the respiratory chain, thereby limiting the damage of reactive oxygen species during the reperfusion phase of ischemia-reperfusion injury commonly seen in cardiac surgeries.In this manuscript, Ahmad and colleagues very clearly show that the addition of MitoSNO or diazoxide to hyperkalemic cardioplegia are protective in both an isolated heart Langendorff model of global ischemia and with a cellular isolated myocyte ischemia-reperfusion model. When both diazoxide and MitoSNO were combined, Ahmad and colleagues predicted a synergistic effect to provide additional cardioprotection. However, this was not the case, as the combination was actually detrimental to cardioprotection. Each compound alone provided increased cardioprotection compared with the combined application.The clinical applications from these findings cannot be overstated. Advancing cardioplegia formulations for strategies aimed at improved cardioprotection are paramount to furthering our technical expertise in cardiac surgeries utilizing cardiopulmonary bypass. We applaud Ahmad and colleagues in this important pursuit, and their key findings in this manuscript lay the groundwork for clinical trials testing new variations of cardioplegia to now include MitoSNO in our arsenal of cardioprotective agents.


Cardiac alterations in structure and function, namely, the left ventricle, have been intensely studied for decades, in association with aging. In recent times, there has been keen interest in describing myocardial changes that accompany skeletal muscle changes in older adults. Initially described as a cardio-sarcopenia syndrome where alterations in myocardial structure were observed particularly among older adults with skeletal muscle sarcopenia, investigations into this syndrome have spurred a fresh level of interest in the cardiac-skeletal muscle axis. The purpose of this perspective is to summarize the background for this “syndrome of concern,” review the body of work generated by various human aging cohorts, and to explore future directions and opportunities for understanding this syndrome. The traditional view of cardiovascular aging is that of age-related adaptations in the heart characterized by increased left ventricular (LV) mass (LVM) and LV hypertrophy (LVH), which are often secondary to increased systolic blood pressure mainly mediated by arterial stiffening , 2. ThesSkeletal muscle sarcopenia occurs with aging but may be accelerated in heart failure states . In advaage-related yet age-independent processes that mediate the cardiac and skeletal muscle systems in older persons.To date, observations pertaining to the cardiac muscle-skeletal muscle axis among non-heart failure cohorts have provided useful insights . In a poThe observations seem to run counter to the dogma of aging-associated LVH, especially in the context of hypertension which dominates aging. Traditionally, cardiac aging has been associated with increased LV wall thickness, with or without myocyte hypertrophy , 17. HigIn contrast, data from sarcopenic subjects suggest that the spotlight on “LVM” could be widened to include the “lower” end of the LVM spectrum. The observed correlates between LVM and specific measurements of skeletal muscle mass/function, emphasize a need to consider the skeletal muscle system as a possible variable in the evaluation of LVM, in addition to body surface area which is routinely calculated in indexed LVM measurements. This may be particularly important in clinical studies where older adults are the focus. Among older adults, there may be interactions between skeletal muscle sarcopenia and LVM. Aging appears to be associated with lower LVM among sarcopenic subjects , 7, suggThe mechanism through which low LVM occurs in the setting of sarcopenia is unknown but potentially intriguing. Studies from autopsy specimens reveal that aging is associated with progressive attrition of myocyte numbers, in addition to hypertrophy of the remaining myocytes . While mRecent literature has shown that patients with HF have worse muscle function and atrophy, because of pathological alterations including altered metabolism, energetics, and decreased oxidative capacity –27. PossMost of the literature that are involved with dysregulated skeletal muscles in clinical HF have provided us with some understanding of possibly shared pathways. It is therefore reasonable to suggest that a cross-talk may in fact pre-exist even before clinical CVD. Conjecturally, the cardio-sarcopenia syndrome likely results from a framework of partially shared pathways leading to the loss of functional mass involving more than one organ system, with a predilection for HF development. As there is a dearth of longitudinal studies tracking skeletal muscle mass and cardiac function prospectively, any suggestion of a causal link between the two remains speculative. Nevertheless, the co-occurrence of skeletal muscle sarcopenia and myocardial perturbations in older adults without and with co-morbidities observed by us and others may be consistent with common upstream pathological pathway (or pathways) associated with aging.Recently, a chronic low-grade inflammatory state known as “inflammaging” has been described in older adults  that is Insulin resistance features heavily in the biochemical cross-talk between the musculoskeletal and cardiovascular systems. Decreased mitochondrial function and increased inflammatory and oxidative stresses that are observed with skeletal muscle aging induce muscle atrophy and insulin resistance . The latGiven the increased incidence of HF among older adults with increased risk of sarcopenia, these additional insights would support early preventative and/or therapeutic strategies that target specific aspects of skeletal muscles, potentially benefitting frail older adults who have yet to develop heart disease. For one, it highlights the potential of using screening tools such as SARC-F to identify older population with sarcopenia as an approach to detect early cardiac dysfunction in the community . The carWhen considering the potential for scalability for case detection of older adults with cardio-sarcopenia syndrome in the geriatric population, detection tools should be easily accessible, safe with minimal radiation, non-invasive and robust. Currently, muscle mass can be estimated using bioelectrical impedance analysis (BIA) or dual-energy X-ray absorptiometry (DEXA) , 51, whiImportantly, some of these tools such as DEXA for body composition can be tagged onto existing imaging procedures for osteoporosis assessment of bone mineral density. Where available, the use of validated multi-frequency BIA facilitates access to measurement of muscle mass in the community setting, Lastly, as per the diagnostic algorithms of recent consensus statements for sarcopenia, the assessment of handgrip strength using a handheld dynamometer allows detection of “possible sarcopenia” defined by low muscle strength, circumventing the need for muscle mass measurement . Taken tChanging the focus from disease management to prevention is a paradigm shift that calls attention to the need for a systems approach to tackling cardiac aging and its complexities. While current HF guidelines recognizes the intimate link between sarcopenia and heart failure, more granular upstream preventative actions before the onset of clinical heart disease can potentially avert joint deteriorations in both organ systems. It is therefore timely to advocate stronger population-based preventative efforts for improving the health of older adults.Exercise is important for maintaining and promoting skeletal and cardiac muscle health. Resistance training is effective for inducing skeletal muscle growth in older adults –57. In aDietary protein constitutes a primary nutrient for maintenance and growth of skeletal muscles . To combAngiotensin-converting enzyme inhibitors (ACE-I) are routinely prescribed to patients with hypertension, HF and diabetes due to their beneficial effects on the vasculature and cardiovascular outcomes. At the molecular level, ACE-I promotes glucose uptake  and suppOn the other hand, sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently been shown to confer renal and cardiometabolic benefits in diabetic and non-diabetic subjects –73 but mFirstly, there is a need for mechanistic understanding of the cross-talk between the various components of body composition and the cardiac muscles. Earlier research has revolved around obesity and its association with cardiovascular structure and function , 78. WitIn this regard, several studies have already demonstrated increased Framingham score or CVD risk in sarcopenic and/or obese older adults –82. In aSecondly, the cohort of older sarcopenic population should be followed up longitudinally with clear documentation of the changes in their skeletal and cardiac muscles as well as their cardiovascular status. This would provide clarity about the development of the cardio-sarcopenia syndrome in relation to the cardiac structure and function over time, which cannot be accomplished by cross-sectional studies that can only make associations at a single point in time. Concurrent biomarker annotation would provide additional mechanistic insights into the development of cardiac aging , useful Thirdly, appropriate clinical trials should be conducted to evaluate the amount of change that is necessary to impact clinical outcomes. For example, in patients with clinically stable chronic HF (predominantly New York Heart Association class II or III), resistance exercise training can improve muscle strength , 86. MorIn conclusion, the concept of cardio-sarcopenia has evolved from a syndrome which describes the coexistence of alterations in myocardial structure with skeletal muscle sarcopenia in older adults to portend pathophysiologic derangements in the cardiac-skeletal muscle axis. Emerging evidence implicating the involvement of adipose tissue, such as sarcopenic obesity , highligDRL, WSL, and ASK contributed to the conception and design of the manuscript. RST, DRL, WSL, and ASK performed literature critiques and contributed to the writing of the manuscript. All authors critically reviewed previous drafts and approved the final draft for submission.


The Enhanced Recovery After Surgery (ERAS) program is based on perioperative medical optimization, including pre-admission counseling, pain relief, carbohydrate intake, thromboembolism prophylaxis, standard anesthetic protocol, optimized intraoperative fluid administration, recovery of normal gastrointestinal function and early mobilization.The main objectives of the ERAS program are to reduce the length of hospital stay after surgery and accelerate the return of patients to normal daily activities without increasing complications, hospital readmission rates and cost.The ERAS program has been adopted in several surgical specialties and is associated with faster and safer recovery, better quality of life and patient satisfaction.The process of implementing this program involves a multidisciplinary team and all units dealing with the surgical patient.Postoperative adverse events, venous thromboembolism is an example, are associated with longer hospital stay and higher mortality rates. Furthermore, factors such as postoperative pain and resumption of bowel function continue to be barriers to early discharge and return to daily activities.The program provides safe, high-quality perioperative care and should become standard practice for all women undergoing elective gynecological surgery.Pre-admission counseling with information about the surgical procedure, anesthesia and postoperative care should be provided.Light meals can be taken up to six hours before surgery and clear liquids can be given up to two hours before surgery.Oral carbohydrates should be given two to three hours before induction of anesthesia.Bowel preparation should not be routinely performed.Perioperative thromboembolic prophylaxis should include dual-modality prophylaxis  depending on the indication in each case.Intraoperative fluid overload should be avoided by adopting goal-directed therapy.Hypothermia should be avoided with intraoperative use of thermal blankets, circulating-water garments and warming of intravenous (IV) fluids.The use of drains, tubes and catheters should be avoided. If indispensable, their use should be limited to the shortest duration needed.Incisional infiltration with liposomal bupivacaine or bupivacaine should be incorporated into all ERAS protocols as a component of multimodal analgesia.Postoperatively, patients can drink immediately after surgery. Intravenous fluids should be discontinued when patients demonstrate ability to maintain oral hydration with at least 500 mL of oral fluid intake.Early mobilization and feeding should be encouraged.Multimodal opioid-sparing analgesia is recommended postoperatively, with greater emphasis on non-opioid drugs such as nonsteroidal anti-inflammatory drugs, acetaminophen, gabapentin, and dexamethasone.Multimodal approach to prevention and treatment of postoperative nausea and vomiting should be considered, with intraoperative use of at least two agents from different classes of antiemetics.https://erassociety.org/) program represents a paradigm shift in conventional perioperative care, replacing, when necessary, some traditional practices with evidence-based practices and achieving better surgical quality, clinical improvements and lower costs to the health system. The program is based on perioperative optimization, including preoperative counseling, pain relief, carbohydrate intake, thromboembolism prophylaxis, standard anesthetic protocol, optimized fluid administration, recovery of normal gastrointestinal function, and early mobilization.The Enhanced Recovery After Surgery .There are currently no definitive guidelines for surgical patients regarding protein requirements, but a postoperative high-protein diet may reduce complications, and immunologic nutrition and arginine supplementation have shown promising results over regimens of heterogeneous nutrition.Preoperative bowel preparation has traditionally been used to decrease postoperative infectious morbidity, including anastomotic leak after bowel surgery. Although this benefit has yet to be unequivocally proven, in addition to patient dissatisfaction, its use has been associated with preoperative dehydration and electrolyte abnormalities that can hamper postoperative recovery. Quality data from studies in colorectal surgery have shown that mechanical preparation alone does not reduce postoperative morbidity and should be abandoned.Bowel preparation with oral antibiotics may decrease infection rates in colorectal surgery, but high-quality evidence to support its use in gynecology is lacking.Surgeons who recommend bowel preparation should limit its use to patients with a colon resection planned. In such cases, the use of oral antibiotics alone should be considered or combined with mechanical bowel preparation.Perioperative thromboembolic prophylaxis should include dual-modality prophylaxis and commence before induction of anesthesia.In the ERAS protocol, patient warming techniques are used since the preoperative period in order to minimize the initial drop in core temperature during anesthetic induction. These techniques, which include the intraoperative use of thermal blankets, circulating-water garment and warming of IV fluids, have shown to be effective in preventing hypothermia and should be continued throughout the surgery and in the post-anesthesia care unit.Adequate control of body temperature is critical, because intraoperative body temperature below 36°C can lead to adverse intraoperative and postoperative outcomes, including coagulopathy, with higher risk of bleeding, impaired drug metabolism and oxygen transport, increased peripheral oxygen uptake, cardiac morbidity, and higher risk of surgical site infections.The ERAS protocol recommends the limited use of drains, tubes and catheters, but if they are indispensable, the use should be limited to the shortest duration required.As for peritoneal drains, they should be considered in the ERAS protocol when there is a greater likelihood of postoperative pelvic collections, concerns about bleeding despite meticulous hemostasis, or very low intestinal resections without concomitant temporary intestinal deviation.Postoperatively, the recommendation is to remove urinary catheters within 24 hours after surgery, with some advocating removing them even earlier.Advances in anesthetic drugs and the expansion of outpatient care allowed the application of some of the principles of outpatient surgery to major surgery in order to mitigate the negative effects of surgical stress and pain, reduce side effects related to anesthetics and accelerate recovery.Regional anesthesia with or without concomitant general anesthesia has been associated with rapid awakening and decreased systemic opioid need.Maintaining euvolemia is one of the principles of the ERAS program.To achieve intraoperative euvolemia, the ERAS protocol recommends avoiding intraoperative fluid overload, minimizing crystalloids and increasing the use of colloids. If a patient is hypotensive but at the same time euvolemic , the use of vasopressor rather than liberal administration of crystalloids is encouraged.Postoperatively, patients can drink fluids immediately after surgery, and IV fluids are stopped when they are able to maintain oral hydration .In the ERAS protocol, pain management begins before the incision. This theory is based on the concept of preemptive analgesia, in which analgesics block the activation of pain receptors before they are activated by the presence of noxious stimuli, resulting in superior pain control and decreased need for analgesics. A multimodal approach that incorporates the preoperative use of gabapentin, oral or IV cyclooxygenase 2 (COX-2) inhibitors (celecoxib or parecoxib), and oral or IV paracetamol has been associated with reduced postoperative opioid use, therefore, it is commonly used in ERAS protocols.The use of opioids has traditionally been associated with increased PONV, compromised bowel function, delayed mobilization due to mental sensory changes, and increased pulmonary morbidity due to respiratory drive depression, in addition to a higher risk of dependence, leading to associated financial and social costs.In addition to opioid-sparing analgesia, the ERAS protocol also adopts a multimodal approach for the preventive treatment of PONV, which includes intraoperative use of at least two agents from different classes of antiemetics. These classes of antiemetic drugs include 5HT3 antagonists, NK-1 antagonists, corticosteroids, antihistamines, anticholinergics, butyrophenones, and phenothiazines. Additional strategies to decrease PONV include the use of propofol infusion and less use of opioids.Early mobilization is a vital component of the ERAS protocol, as it protects against muscle and physical conditioning loss by avoiding prolonged bed rest and immobility. As a result, it helps to reduce pulmonary and venous thromboembolic complications, improves insulin resistance, and helps to reduce hospital stay.The return of bowel function is usually the last milestone reached before hospital discharge after a laparotomy. Among the factors influencing the return of bowel function are the use of opioids, the balance of venous fluids, the extent of peritoneal disease in the case of cancer patients, the complexity of surgery, the need for blood transfusion and postoperative abdominopelvic complications.The implementation of minimally invasive surgery reduces the rate of postoperative ileus, but not all patients are candidates for this surgical approach. Among patients who need laparotomy, interventions that stimulate the enteric nervous system and reduce the use of opioids, such as early feeding, coffee consumption and chewing gum have shown to be effective in reducing the time for the return of bowel function in some studies. Although the use of chewing gum is safe and inexpensive, a large, recent, well-conducted randomized trial has shown no benefit. The consumption of coffee in the postoperative period has shown to reduce from 30% to 10% the rate of postoperative ileus in women undergoing gynecological cancer surgery. Furthermore, measures such as early ambulation and modal analgesia have shown a two to five times decrease of the rate of postoperative ileus.The ERAS protocol also considers the possibility of using laxatives in order to accelerate the return of gastrointestinal function, since an earlier time for the first evacuation was observed when bowel stimulation with oral osmotic laxatives was performed within six hours after abdominal hysterectomy, with no change in pain and PONV scores.The principles of the ERAS protocol are applicable to all surgical specialties, and constant innovation must be the keynote to allow for the improvement of processes. The implementation of the ERAS program represents a paradigm shift in the perioperative management of surgical patients and is a multidisciplinary evidence-based approach. The program is clinically effective and impacts patient outcomes, providing a safe, high-quality approach and cost-effective perioperative care. In addition, a successful program can lead to faster and safer recovery and better quality of life and patient satisfaction. Therefore, the ERAS program should become standard practice for all women undergoing elective gynecological surgery.National Specialized Commission on Ginecologic Endoscopy of the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO)President:Paulo Augusto Ayroza Galvão RibeiroVice-President:Mariano Tamura Vieira GomesSecretary:Thomas MoscovitzMembros:Fabio OharaFrancisco Eduardo ProtaGustavo Anderman Silva BarisonJean Pierre Barguil BrasileiroKarin Kneipp Costa RossiLuciano GibranLuiz Flavio Cordeiro FernandesRaquel Papandreus DibiRaquel Silveira da Cunha AraújoRicardo Bassil LasmarRita De Cássia Barbosa Tavares SantosRomulo Muller dos Santos MeloNational Specialized Commission on Endometriosis of the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO)President:Julio Cesar Rosa e SilvaVice-President:Helizabet Salomao AbdallaSecretary:Márcia Mendonça CarneiroMembros:Carlos Alberto PettaCarlos Augusto Pires Costa LinoCorival Lisboa Alves de CastroEduardo SchorJoão Nogueira NetoJoão Sabino Lahorgue da Cunha FilhoMarco Aurélio Pinho de OliveiraMarcos TcherniakovskyMaurício Simões AbrãoOmero Benedicto Poli NetoRicardo de Almeida QuintairosSidney Pearce FurtadoNational Specialized Commission on Oncological Gynecology of the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO)President:Walquíria Quida Salles Pereira PrimoVice-President:Suzana Arenhart PessiniSecretary:Jesus Paula CarvalhoMembros:Angélica Nogueira RodriguesCaetano da Silva CardialDelzio Salgado BicalhoEduardo Batista CandidoEtelvino de Souza TrindadeFernando MalufFrancisco José Cândido dos ReisGeorgia Fontes CintraMarcia Luiza Appel BindaMirian Helena Hoeschl Abreu MacedoRenato Moretti MarquesRicardo dos ReisSophie Françoise Mauricette DerchainHeloisa de Andrade Carvalho


The focus of precision medicine is providing the right treatment to each unique patient. This scientific movement has incited monumental advances in oncology including the approval of effective, targeted agnostic therapies. Yet, precision oncology has focused largely on genomics in the treatment decision making process, and several recent clinical trials demonstrate that genomics is not the only variable to be considered. Drug screening in three dimensional (3D) models, including patient derived organoids, organs on a chip, xenografts, and 3D-bioprinted models provide a functional medicine perspective and necessary complement to genomic testing. In this review, we discuss the practicality of various 3D drug screening models and each model’s ability to capture the patient’s tumor microenvironment. We highlight the potential for enhancing precision medicine that personalized functional drug testing holds in combination with genomic testing and emerging mathematical models. Precision medicine has become synonymous with genomic medicine , 2, yet As illustrated by the SHIVA trial and SIGNATURE program discussed above, possession of an actionable mutation and eligibility for genome-matched treatment aside, biomarker presence does not alone guarantee therapeutic success. Many clinically important driver mutations are therapeutic targets  present in both benign and malignant conditions , and a rClinicalTrials.gov for relevant trials using the terms: next-generation sequencing (NGS), or drug screening AND organoid, PDO, xenograft, PDX, patient-derived, organ on a chip, OOC, 3D bioprinted, microfluidic, drug screen. We also included trials cited in relevant articles that we judged to be important. We searched PubMed for reviews and original research papers published between 1 January 2015 and 1 February 2022 using the keywords: chemosensitivity, cancer organoids, cancer xenografts, organ on a chip, microfluidic cancer model, 3D printed, 3D bioprinted, patient-derived organoids, patient-derived cancer xenografts, patient-derived organ on a chip, functional precision medicine, functional precision oncology, metastasis models, and cancer drug screening models. We incorporated publications cited in the articles from our search that we judged to be important. The reference list was generated on the basis of ingenuity and pertinence to the topic of this review.In this review, we provide an overview of functional precision medicine, discuss the technological advances of tumor models for drug testing, and highlight the latest clinical trials that incorporate genomics and functional drug screening. We searched The first report of drug sensitivity testing using primary tumor tissues from patients to predict response to chemotherapeutic agents was published over 60 years ago by Dr. Jane C. Wright, an African-American physician and the only female founding member of the American Society of Clinical Oncology (ASCO) . Wright’in vitro renditions of CSRAs, including the human tumor stem cell assay , immune cells, cancer associated fibroblasts, and angiogenic vascular cells among others. The stromal cells interact with each other and tumor cells by secreting chemokines, growth factors, and regulatory miRNAs, all implicit in cancer progression . Endothepatient-derived organoids (PDOs) are derived from patient tissue embedded in a matrix, cultured in suspension, or grown as a co-culture model. Organoids are a 3D alternative to 2D cell culture that better represent the tumor microenvironment  . PDOs brA model that falls beside patient derived organoids is the patient-derived explant (PDE) model. PDEs are generated when freshly resected tissue is promptly submerged in media or grown on a matrix or sponge in media and used for drug screening, thus preserving the original tumor architecture and intact stroma. The Histoculture Drug Response Assay (HDRA) and other explant platforms were successful in 1990s and 2000s, but have not advanced since then, likely because patient-derived explants only survive intact for short periods of time .in vivo perspective, recapitulates tumor heterogeneity, and allows for measurement of pharmacokinetic and pharmacodynamic parameters.Patient-derived xenografts (PDXs) typically involve implanting patient tumor cells in immunodeficient mice; immunocompromised mice are necessary to prevent rejection of human tumor cells by the host animal’s immune system and improve engraftment success rates . Tumor cin vivo and some features of the tumor are not fully represented including the TME, tumor-host interactions, and local growth of PDX’s  have also been explored as high throughput alternatives to PDXs that allow for prolonged culture and preservation of the unique disease profiles initially cultured ver time . Pancreaver time . A protover time . Althougin vivo and drugs can be added directly to the zebrafish habitat (The zebrafish patient-derived xenograft model (zPDX) is a high throughput and low-cost alternative to murine models, zebrafish can hatch 150–200 eggs per week, and display a high level of genetic and molecular pathway conservation with humans. Shortcomings of the zebrafish model include high mortality after injection and the difference in body temperature between zebrafish and humans. Xenotransplantation procedures using larval zebrafish recipients are conducted below 37 degrees, and at those temperatures the tumor cells fail to proliferate and form tumors at the same rate that they do in immunocompromised mice or human patients , 50. The habitat . Immune  habitat . FurtherOrgan-on-a-chip (OOC) technology, also known as microphysiological systems, is a microfluidics-based approach to disease modeling composed of a network of channels that allow continuous perfusion of cells grown on a basement membrane mimicking substance. The microfluidics model allows for simultaneous culture of multiple cell types on the same chip and is designed for precise control of chemical gradients as well as drug, signaling molecule, and media delivery . OOC tecIn pancreatic cancer, microfluidic chips have been used to study metastasis  and humaex vivo conditions (which the authors believe to be an effect of increased cellular stress in the ex vivo model), but not in the OOC platform. OOC organotypic slice culture response to antiandrogen therapy in prostate cancer and cisplatin treatment in breast cancer modeled drug response in paired PDXs  of tumor cells is emerging as another technology with potential in functional precision medicine (FPM). Explained in depth by Liu et al. , CR invoInduced pluripotent stem cells (iPSC) have also been considered as a potential study model for preclinical oncology drug testing. iPSCs are somatic cells reprogrammed by four transcription factors such that they can differentiate into multiple cell lineages and organoid culturing of iPSCs mimics tumorigenesis and have been established for multiple organs. iPSCs provide a more reliable source of cells compared to traditional 2D culture and could overcome issues with genetic drift that occur in long term primary culture . Despitevia the transcriptome) was developed, which employs the genetic interactions of drug targets to identify individualized therapies for cancer patients. Based on the pre-treatment transcriptomic data of 35 clinical trials using targeted and immunotherapy to treat 10 different cancer types, this framework predicted patient response in 80% of the clinical trials examined, suggesting that transcriptomics could be used to guide precision medicine treatment decision-making  models are similar to mathematical models and are based on the concept of artificial intelligence (AI) that computers learn through experience and can track and predict drug response, cancer risk, and cancer outcomes over time. ML is unique because multiple datasets can be integrated, including genomic, transcriptomic, proteomic, and image-based information to identify trends across the datasets. ML algorithms can recognize patterns not necessarily evident to the human eye and identify new biomarkers . ML is bMachine learning has been applied to accurately predict the efficacy of molecularly targeted and non-specific chemotherapy drugs in cancer cell lines and shows promise for translation into the clinical realm . A deep in vitro functional drug screening, though the 3D environment of PDOs and PDXs has the potential to more faithfully recapitulate the disease state and patient response to various therapeutics. Previous studies using a similar single-cell automated imaging assay-guided approach demonstrated feasibility for clinical integration and led to improved treatment outcomes for hematologic malignancies  and PDX  models, but these technologies are still gaining speed in the clinical functional medicine arena. The EXALT study was the first prospective precision medicine trial to use a personalized functional medicine assay to guide therapeutic decision making. This study employed an image-based single-cell drug screen platform with automated high content microscopy and image analysis  to test treatment for patients with advanced aggressive hematologic cancers. Fifty-four percent of those treated according to single cell functional precision medicine (scFPM) results experienced 1.3-fold improvements in PFS compared with prior therapies, and 40% of these patients had outstanding responses that lasted 3-fold longer than predicted for their disease  and the assay demonstrated its utility in a pilot study of metastatic CRC . A recenA CLIA certified PDO drug assay by SEngine Precision Medicine recently reported a high concordance of drug sensitivity with known genomic anchors as well as sensitivity to target agents in the absence of known genomic biomarkers –100. Thein vivo mimics patient drug resistance (NCT02517892). The Tumorgraft study (NCT02752932) utilized murine PDX models to screen four compounds for each patient. Unfortunately, average time to engraftment was 89.2 days. Of the two eligible living patients who underwent Tumorgraft guided therapy, one patient failed to respond to a therapy that was efficacious in their corresponding xenograft model, and the other patient responded to the compound most potent in their matched xenograft model . The trial is employing zebrafish avatars to perform a chemosensitivity assessment on each patient, with PDX-guided treatment conclusions available within 1 week of engraftment. There are also two current clinical trials utilizing chick embryos as a host model system for PDX drug testing in those with renal cell carcinoma (NCT04602702) and urogenital malignancies (NCT03551457). The chick chorioallantoic membrane (CAM) PDX model is a lower cost, high throughput alternative to murine models that displays enhanced tumor take rate compared to murine models, conserved tumor heterogeneity, and a strong representation of metastasis; the CAM model is excellently reviewed in Chu et al. . One curThough conditional reprogramming and induced pluripotent stem cell technologies still remain in development, these methods are gaining footage in the clinical trial arena. Currently, one clinical trial is utilizing drug screening in PDX and mini-PDX platforms to guide treatment and will be performing CR on patient cells to follow up on tumor drug susceptibility testing (NCT04373928). An ongoing NCI protocol is combining genetic testing with reprogramming of patient cells to iPSCs in order to generate cancer antigen-specific T cells (NCT03407040). In another trial, iPSCs will be derived from patients who experience cardiotoxicity after thoracic radiation in order to identify mechanisms of radiation-induced cardiotoxicity (NCT04674501). Finally, among neurofibromatosis type 1 population, agents are being screened in patient-derived iPSC lines with different genotypes to identify drugs capable of reversing disease phenotypes (NCT03332030).via WGS, bisulfite sequencing, and protein quantification, then a multiomic machine learning algorithm was applied to detect early-stage CRC. This machine learning approach using cell-free DNA demonstrated high specificity and sensitivity for detection of early-stage disease in a CRC cohort  was 2.1%; for trials using biomarkers, the probability of success was 10.7% . SimilarThe practicality of functional precision medicine poses a major challenge; currently, most resected tissue is rapidly fixed for histology or processed for sequencing, preventing further use for FPM assays. Likewise, hospitals abide by a variety of protocols governing tissue handling after resection; lack of standardization of these processes could ultimately affect the implementation of FPM assays moving forward. Drug concentrations and drug treatment duration in patient-derived models and patients themselves frequently differ . Some moNot only must drug screening join NGS and AI to advance FPM, but combination therapies and mechanisms of resistance must continue to be explored. Coupling FPM assays with molecular/genomic screening can elucidate not only mechanisms of primary and acquired resistance, but more importantly provide insight on how to overcome them. Forthcoming precision medicine trials are focusing on addressing treatment combinations in areas of unmet clinical need. To overcome acquired drug resistance to single-agent therapy, NCI-ComboMATCH, the next phase of the NCI-MATCH trial (which consisted mostly of single agents), is implementing genomically directed targeted agent combinations supported by preclinical PDX and cell line derived xenograft data . In the Another FPM technique that can assist precision medicine decision-making is BH3 profiling, which assesses apoptotic priming and is used to predict response to chemotherapy and targeted combinations . ApoptosThe ongoing I-PREDICT study assigned personalized combination treatment regimens based on DNA sequencing results, NGS of circulating tumor DNA, PD-L1 status, microsatellite instability status, and tumor mutational burden. I-PREDICT observed that targeting more molecular alterations was correlated with significantly improved disease control rates and longer PFS and overall survival (OS) . Of the 83 patients in this study who received treatment, each molecular profile and most therapeutic regimens were unique, underscoring the need for personalized therapy and the major potential of combination therapies . On the ex vivo drug testing (NCT03896958).Once FPM technologies are optimized, accessibility to clinical trials still presents a major hurdle. A study based out of Memorial Sloan Kettering utilizing the MSK-IMPACT comprehensive sequencing assay found that although 37% of participants had clinically actionable alterations, only 11% of the first 5,009 patients tested were enrolled in a clinical trial involving a molecularly targeted agent, reflecting difficulties with geographical accessibility to clinical trials and patient preference . In an aAs PDX models continue to evolve, 3D personalized drug screening coupled with NGS is emerging as a multipronged approach to guide treatment decision making. Developing OOC and 3D printed models will provide more ethical alternatives to PDXs for personalized drug screening in the future and the application of ML to data garnered by way of these technologies will uncover a wealth of knowledge in the years to come. Spatial omics is likewise evolving to further elucidate the complexity of the tumor microenvironment. Coupled with AI analysis, spatial omics technology is capable of linking pathology images with spatial gene expression profiles and spatial maps of tumor samples will uncover new potential treatment avenues . Single-GN and CC conceived and structured the content. All authors contributed to the writing and editing of the article, and approved the submitted version.The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cervus elaphus) spatial behavior by testing three a-priori hypotheses: (i) red deer are expected to avoid areas used by livestock, as well as adjacent areas, when livestock are present, albeit (ii) red deer increase the use of these areas when sheep and goats are temporarily absent and (iii) there is a time-lagged disruption in red deer spatial behavior when conservation grazing practice ends. Using GPS-telemetry data on red deer from a German heathland area, we modelled their use of areas grazed by sheep and goats, using mixed-effect logistic regression. Additionally, we developed seasonal resource selection functions (use-availability design) to depict habitat selection by red deer before, during, and after conservation grazing. Red deer used areas less during conservation grazing throughout all times of the day and there was no compensatory use during nighttime. This effect mostly persisted within 21 days after conservation grazing. Effects on habitat selection of red deer were detectable up to 3000 meters away from the conservation grazing sites, with no signs of either habituation or adaption. For the first time, we demonstrate that conservation grazing can affect the spatio-temporal behavior of wild herbivores. Our findings are relevant for optimizing landscape and wildlife management when conservation grazing is used in areas where wild herbivores are present.Conservation grazing uses semi-feral or domesticated herbivores to limit encroachment in open areas and to promote biodiversity. However, we are still unaware of its effects on wild herbivores. This study investigates the influence of herded sheep and goats on red deer ( Semi-natural open areas such as grasslands, heathlands or wetlands often act as important refuges for rare, highly specialized plant and animal species  are large ungulates that display grazing-type feeding behavior and often utilize open areas such as grass- and heathland for foraging (Wolff and Horn −1). Moreover, Riesch et al.  red deer are expected to avoid areas used by livestock, as well as adjacent areas, when livestock are present, albeit (ii) red deer increase the use of these areas when sheep and goats are temporarily absent and (iii) there is a time-lagged disruption in red deer spatial behavior when conservation grazing practice ends. A potential displacement of red deer by targeted sheep-grazing—either due to resource competition or direct disturbance—would be highly relevant for both, wildlife management and conservation of semi-natural open areas.Corynephorus canescens). These open areas are surrounded by forest stands of different age and species composition, mainly consisting of pine (Pinus sylvestris) and birch (Betula pendula). Glücksburger Heide itself is situated in an agricultural landscape. Red deer are very abundant in the study area, with an estimated density of 11.6 individuals per km². Hunting activities aimed at red deer, wild boar (Sus scrofa) and roe deer (Capreolus capreolus) include two driven huntsWe conducted our research at Glücksburger Heide, a 7000-hectare former military training site located in Saxony-Anhalt, Germany   and goats (German Edelziege) for conservation grazing on different successional grass- and heathland areas within the study area. From 2016 to 2018, conservation grazing took place at three distinct sites comprising 62, 22, and 102 hectares, respectively Fig. . From 20Between 2014 and 2018, a total of 25 red deer  were caught individually, using an immobilization gun (stags) or a drop-net-catch system (hinds) at Glücksburger Heide. The animals were fitted with GSM-GPS collars , set to record their position every two hours, and then released.We used a two-step statistical approach to investigate the spatial behavior of red deer at Glücksburger Heide before, during, and after conservation grazing. We first fitted mixed-effect logistic regression to model red deer use of the conservation grazing sites and to gain insights into how conservation grazing directly affects the likelihood of presence on dry heathland as foraging and mating grounds. In a second modelling approach, we built resource selection functions  recover from displacement by hunting dogs as soon as one day after the event, while Sunde et al.  and also in winter (November to January). Red deer display seasonal variations in their spatio-temporal behaviour , respectively. For the winter regression model, the rutting period and calving period variables did not apply. For the summer regression model, we fitted multiple model candidates with and without the rutting or calving period as included effects. The final model was selected by comparing AIC values  in the same manner and also featured variables for time of day , rutting period, and calving period. The data were then also split into summer and winter. We then expanded this database of GPS relocations by adding available locations. Resource selection functions use recorded locations of animals and locations available to them to investigate whether sites with certain properties are being selected  and food resources  were assigned to all used and available locations. Previous research has shown that spatial behaviour in large herbivores is mainly governed by a trade-off between the basic needs for forage and cover , was used as a response. Continuous variables representing cover (tree cover), food resources (NDVI) and distance to the conservation grazing sites, as well as the categorical variables time of day , treatment  and the binary variables for the rutting and calving periods , were used as predictors , respectively. We performed model selection based on AIC  of the final regression models were used to formulate seasonal resource selection functions, which commonly take an exponential form . During the stricter blocked cross-validation, the summer RSF performed worse (Spearman’s rho: 0.891)—as expected compared to random cross-validation , areas close to the conservation grazing sites were preferred the most before sheep grazed there . As sheep-grazing started, red deer presence shifted further away and continued to do so in line with ongoing conservation grazing; after conservation grazing, it either remained static or slightly shifted back within the 3 weeks considered here. The most striking change in preference occurred during the daytime  scent can even provoke symptoms of physical stress or lead to avoidance of the affected areas , red deer do not resort to their original spatio-temporal behavior after conservation grazing stops. Their use of the conservation grazing sites remains low at all times of the day in summer but partially recovers during the daytime in winter. We make a similar observation for habitat selection in terms of distance to conservation grazing sites: Selection is low after conservation grazing ceases during the summer but partly recovers in the winter. One important factor could be the overall greater selection of open areas by red deer, leading to faster re-utilization in winter. However, the observed seasonal differences might also be induced by additional factors such as the removal of tree saplings during summer or increased hunting pressure during winter, as well as varying amounts of food resources in the surrounding areas throughout the year. We conclude that the effects of conservation grazing on the spatio-temporal behavior of red deer in Glücksburger Heide persist for some time after conservation grazing activities stop. However, the design of this study does not allow us to make clear inferences about the exact temporal dimensions of enduring behavioral changes. Nonetheless, it should be noted that during the following 21 days, both the direct presence on the sites and the overall habitat selection significantly differ from what is observed before conservation grazing. This delay in revisiting these areas might be caused by the already mentioned depletion of forage vegetation, remaining scents, or persistent spatial memory of the disturbance, the latter of which might push these animals to other suitable areas they continue to use after sheep-grazing has stopped. Aspects of spatial familiarity Piper  might alOur findings are supported by good results during the two different cross-validation approaches. The resemblance of the overall patterns between the different seasonal models provides additional confidence that our results reflect the veridical effects of conservation grazing on the spatio-temporal behavior of red deer at Glücksburger Heide. Nevertheless, the structural composition of a landscape and the overall availability of different land-cover types can essentially influence general spatial behavior : Godvik et al. Our findings indicate that interactions between wild and domesticated herbivores should be considered in conservation planning for semi-natural open areas such as dry heath- or grasslands. Both conservation grazing with domesticated herbivores (Dostálek and Frantík Supplementary Information