Plant rhizospheres encompass a dynamic zone of interactions between microorganisms and their respective plant hosts. For decades, researchers have worked to understand how these complex interactions influence different aspects of plant growth, development, and evolution. Studies of plant-microbial interactions in the root zone have typically focused on the effect of single microbial species or strains on a plant host. These studies, however, provide only a snapshot of the complex interactions that occur in the rhizosphere, leaving researchers with a limited understanding of how the complex microbiome influences the biology of the plant host. To better understand how rhizosphere interactions influence plant growth and development, novel frameworks and research methodologies could be implemented. In this perspective, we propose applying concepts in evolutionary biology to microbiome experiments for improved understanding of group-to-group and community-level microbial interactions influencing soil nutrient cycling. We also put forth simple experimental designs utilizing -omics techniques that can reveal important changes in the rhizosphere impacting the plant host. A greater focus on the components of complexity of the microbiome and how these impact plant host biology could yield more insight into previously unexplored aspects of host-microbe biology relevant to crop production and protection. With growing interest in host-microbe biology, a mixture of new and re-established terms have been developed in recent years to describe complex associations of organisms that are heritable. The concept of the “holobiont” and its “hologenome”   signify There is an extensive history of research detailing the co-evolutionary forces dually acting on plants and their microbial symbionts. For example, research on vesicular-arbuscular mycorrhiza (VAM) has suggested that the highly beneficial symbiosis between the plant root and fungal symbiont has driven the diversification of plant root morphology as well as VAM structure and function . In addiSimilar to animal microbiomes, different compartments of a plant can harbor functionally and taxonomically distinct sets of microbiomes—these include the phyllosphere microbiome encompassing the aboveground parts of plants, root, and shoot endophytes (microbiomes colonizing root and shoot tissues), and the rhizosphere microbiome that inhabits soil surrounding plant roots and adhering to root surfaces . AlthougWhile it appears overwhelming to study complex interactions between a microbiome and its host plant, there is growing interest in broadening the concept of heritability to be inclusive of a host and its microbiome . It is cMultilevel selection can be defined as natural selection acting on whole groups of organisms in addition to individuals, as initially proposed by Darwin . During Figure 1)  . A classigure 1) . In the igure 1) . Such a igure 1) . Studiesigure 1) .In the case of the plant rhizosphere, individual and group-level selective pressures constantly interact to shape the phenotype of the rhizosphere, although this is often overlooked when focusing on classical symbiosis studies. If perceptions of symbiosis expand to encompass multiple partnerships, including dozens of microbial taxa, it is then suitable to test the effect of group dynamics on nutrient cycling in the rhizosphere influencing plant growth. A plant growing in nitrogen-limited soils could gain a fitness advantage over competitors by enriching its rhizosphere for microbial communities that enhance nutrient capture and utilization capabilities .Figure 2). While the example illustrates how group dynamics at multiple levels of organization impact the fitness of the plant host, the microbial community, and specific individuals or related cells, the interaction has posed a significant challenge to test experimentally until recent years.For example, actively growing roots could signal for microorganisms that are capable of producing extracellular enzymes that release nitrogen bound in soil organic matter . For proThere are many more components to nutrient cycling that are microbially mediated, with potential group dynamics influencing plant growth. For example, microorganisms such as rhizobia and certain free-living diazotrophs can form groups that fix atmospheric nitrogen through metabolic processes and make the nutrient readily available for plant uptake . In addiThe application of multilevel selection theory to rhizosphere processes, such as nutrient cycling, offers researchers an opportunity to understand how multiple levels of selection shape a plant’s microbiome. Experimental tests of group dynamics in the rhizosphere impacting a plant phenotype are needed to help us understand the role of complex associations of microorganisms in determining plant growth, development, and fitness. In this section, we propose three concepts for experimental designs that could aid in elucidating the role of the rhizosphere microbiome in impacting various plant phenotypes via alterations in nutrient cycling processes.Arabidopsis thaliana could be enhanced by artificially selecting for rhizosphere microbiomes that are known to increase plant biomass production. In a similar study using A. thaliana, flowering time was modified by soil microbiota through repeated selections of rhizosphere microbiomes, which was predicated based on the idea that selection can be performed on a plant’s phenotype while the agents of selection are comprised of the rhizosphere microbiome -Cas can be useful in modifying rhizosphere processes through changes in plant structure and physiology . The CRICurrently, there is a growing interest in developing a broader understanding of host-microbe biology. Similar to human and other animals, different plant compartments harbor distinct microbiomes, which could evolve and adapt with their host to influence the observed phenotypes. In essence, fitness is both influenced by and shared among multiple levels—the individual plant host and groups comprising its microbiome. Thus, the application of evolutionary frameworks, such as multilevel selection, to plant microbiomes could be useful in developing a more robust understanding of host-microbe interactions. Utilizing –omics techniques is key to uncovering potential mechanisms underlying group-level interactions in the rhizosphere. It is conceivable that cross-kingdom signaling dominates rhizosphere processes, which suggests that the definition of heritability should be inclusive of an individual and its associated microbiome. The plant host may influence the composition and function of the resulting microbiome, but microorganisms have the ability to modify plant traits.An applied outcome of studying group-level dynamics in the rhizosphere is the ability to incorporate concepts of the holobiont into plant breeding. Selection efforts that consider rhizosphere microbiomes as an extended phenotype of a plant could help identify potential mechanisms that enrich for subpopulations of the microbiome. These “plant-cultivated” members of the rhizosphere could play essential roles in supporting the development of specific phenotypes of the plant that improve plant growth under biotic or abiotic stress.However, plant genetics may not play a significant role in influencing the microbiome, but instead the plant may be highly susceptible to microbiome effects on plant traits. A greater understanding of how microbiomes influence the observed phenotype of a plant can help to tease apart the effect of environmental variables from biotic factors. For example, in studies involving genotype by environment interactions (G × E), phenotypic variation is assumed to be a result of plant genetics influenced by varying environmental conditions across field sites. In the near future, we expect that the low cost of microbiome sequencing methods will result in the adoption of rapid microbiome diagnostics revealing the role of microbiome variability across field sites in influencing plasticity of the plant phenotypes. In essence, there will likely be a shift toward analysis of genotype by environment by microbiome interactions (G × E × M) in the coming years.Finally, we believe that the current industry focus on examining single microbial isolate effects on plant traits will be replaced with more emphasis on complex interactions involving multiple players. The recent popularity of examining synthetic communities comprised of multiple microbial strains helps to advance microbiome science forward, but it would be beneficial to move beyond cultivation-dependent methods. Applying selective filters to reduce the diversity of complex microbiomes associated with a plant trait could enable more top-down and bottom-up approaches comprised of cultivation-dependent and –independent multi-player interaction studies. While teasing apart the complexity of the rhizosphere will be incredibly challenging, such research could ultimately help develop a better understanding of how rhizosphere microbiomes influence plant growth, development, and fitness.Both authors listed have made direct and substantial contributions to this work and have approved it for publication.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.


Cognitive decline is a painful aspect of normal aging, with enormous clinical, social and economic implications. No effective treatment is available for this aggravating condition, even though preventive measures such as physical exercise, mental activity and balanced diet have been suggested to slow down the cognitive deterioration that begins already in midlife. Last year, Bilkei-Gorzo and co-workers showed that a chronic treatment with tetrahydrocannabinol  restored cognitive functions in aging mice . This stCannabis (marijuana) is still defined as an illicit drug of abuse and previous reviews have described the deleterious outcomes of chronic cannabis use . On theRecently, we found that a single administration of an extremely low dose of THC to old mice improved their cognitive performance in a battery of six different behavioral assays that measured different aspects of memory and learning . The oldCan these surprising neuroprotective effects of ultra-low THC in mice be translated to clinical treatment in aging humans? An appropriate conversion of drug doses from experimental animals to humans should be normalized for body surface area . Hence,


Several publications in the psychological literature support the theory that children are a major source of stress for their parents. Not surprisingly, parents of children with behavior problems—particularly children with attention deficit hyperactivity disorder (ADHD)—experience highly elevated levels of daily child-rearing stresses. Children with ADHD disregard parental requests, commands, and rules; fight with siblings; disturb neighbors; and have frequent negative encounters with schoolteachers and principals. Although many investigations have dealt with parenting stress caused by disruptive children, only a handful of studies have addressed the question of how parents cope with this stress. Those findings are presented, including a series of studies assessing parental distress and alcohol consumption among parents of normal children and ADHD children after the parents interacted with either normal- or deviant-behaving children. Those studies strongly support the assumption that the deviant child behaviors that represent major chronic interpersonal stressors for parents of ADHD children are associated with increased parental alcohol consumption. Studies also have demonstrated that parenting hassles may result in increased alcohol consumption in parents of “ normal” children. Given these findings, the stress associated with parenting and its influence on parental alcohol consumption should occupy a salient position among the variables that are examined in the study of stress and alcohol problems. The idea that children can cause stress in parents is an often-exploited scenario in cartoon pages. “ Dennis the Menace” has tormented his parents and other adults for decades, and Calvin, the little boy in the cartoon series “ Calvin and Hobbes,” kept a record on his calendar of how often he drove his mother crazy. Similarly, in the noncartoon world, the question of whether children cause stress yields numerous raised hands in any group of parents. Indeed, a considerable number of publications in the psychological literature support the argument that children are a major source of stress for their parents .Not surprisingly, parents of children with behavior problems—particularly children with attention deficit hyperactivity disorder (ADHD)—experience highly elevated levels of daily child-rearing stresses . ChildreAlthough many investigations have dealt with parenting stress caused by disruptive children, only a handful of studies have addressed the question of how parents cope with this stress. For example, if stress in general can precipitate alcohol consumption, it would not be surprising to discover that some parents might attempt to cope with their parenting stress and distress by drinking. This article first reviews the relationship between childhood behavior problems and subsequent adult drinking behavior, and then explores the effects of child behavior on parental drinking. The discussion includes a review of a series of studies assessing parental distress and alcohol consumption among parents of normal children and ADHD children after the parents interacted with either normal- or deviant-behaving children.Children with ADHD have problems paying attention, controlling impulses, and modulating their activity level. Two other disruptive behavior disorders—oppositional defiant disorder (ODD) and conduct disorder (CD)—overlap considerably with ADHD. Children with ODD are irritable and actively defiant toward parents and teachers, whereas children with CD exhibit norm-violating behavior, including aggression, stealing, and property destruction. Substantial comorbidity occurs among these disorders, ranging from 50 to 75 percent. A large body of research has demonstrated many connections between alcohol problems in adults and these three disruptive behavior disorders :Children with externalizing disorders are at increased risk for developing alcohol or other drug (AOD) abuse and related problems as adolescents and as adults .Adult alcoholics more commonly have a history of ADHD symptomatology compared with non-alcoholics e.g., .The prevalence of alcohol problems is higher among fathers of boys with ADHD and/or CD/ODD than among fathers of boys without these disorders e.g., .Similarities exist between the behavioral, temperamental, and cognitive characteristics of many children of alcoholics and such characteristics of children with ADHD and related disruptive disorders .In summary, these findings indicate that childhood externalizing behavior disorders are associated with an increased risk of familial alcohol problems, as well as subsequent adult alcohol problems. Furthermore, parental alcohol problems may contribute to a child’s current and future psychopathology. Conversely, a child’s behavior problems may intensify parental drinking, which in turn may exacerbate the child’s pathology. This vicious cycle may result in ever more serious problems for the entire family.As described in the previous section, in families with children with behavior disorders and/or parental alcoholism, both the parents and children appear to have an elevated risk for alcohol-related problems. Researchers have only recently begun, however, to explore the causal mechanisms operating in these relationships. In addition, the research has focused primarily on the effects that parental drinking has on the children and their behavior. Some recent studies, however, have begun to examine the possible effects of deviant child behavior on parental alcohol problems.Researchers and clinicians widely believe that children with behavior problems, particularly those with such externalizing disorders as ADHD, can adversely affect their parents’ mental health . ChildhoDespite the evidence that children with behavior problems cause substantial stress and other dysfunctional responses in their parents, almost no research has investigated whether these parental responses include elevated alcohol consumption and/or alcohol problems. This lack of research is particularly surprising given the well-documented association between adult alcohol problems and childhood externalizing disorders. Several relationships may exist among deviant child behavior, parental stress, and two broad types of dysfunctional responses in parents—emotional problems, such as anxiety and depression , and problem drinking. These hypothesized relationships are shown in the model in Between 1985 and 1995, researchers at the University of Pittsburgh and Florida State University conducted a series of studies examining the relationships described above. Although some of those analyses have examined the influences of parental alcohol consumption on child behavior , most ofThus, all the studies described in this section have employed a similar design and similar measures. The participants, of whom most were parents and all were social drinkers , were recruited for what they believed were studies designed to investigate the effects of alcohol consumption on the way they interacted with children. The participants were told that they would have a baseline interaction with a child, followed by a period in which they could consume as much of their favored alcoholic beverage as they wanted , followed by another interaction with the same child. Each interaction period consisted of three phases: (1) a cooperative task in which the child and adult had to cooperate to solve a maze on an Etch-a-Sketch, (2) a parallel task during which the child worked on homework while the adult balanced a checkbook, and (3) a free-play and clean-up period. In all three settings, the adult was responsible for ensuring that the child stuck to the required task but also was directed to refrain from providing the child with too much assistance.The adult participants were led to believe that the aim of the study was to compare their interactions with the children before and after drinking in order to learn about alcohol’s effects on adult-child interactions. The adults also were told that the child with whom they would interact might be a normal child from a local school or an ADHD child who was receiving treatment in a clinic. In fact, however, all of the children were normal children who had been hired and trained to enact carefully scripted roles that reflected either ADHD, non-compliant, or oppositional behavior (referred to as “deviant children” ) or normal child behavior . The true goal of the study was to evaluate each adult’s emotional, physiological, and drinking behavior in response to his or her first interaction with a particular child and while anticipating a second interaction with the same child.Using undergraduate students as subjects, the first study of the series was designed to evaluate the validity of the concept that interactions with deviant children could induce both stress and stress-related alcohol consumption in adults  . In thatIntriguing as these results were, however, they could not be generalized to parents of children with behavior disorders, because the subjects were single undergraduate students who were not parents. The results did illustrate, however, that child behavior could be used to manipulate adult drinking behavior and that interactions with deviant children were potentially stressful, at least in young adults without parenting experience.Using the same study design, It is notable that these effects were obtained in a sample of parents of non-deviant children. Thus, the results are consistent with other studies showing that parenting hassles can cause distress even in normal families . FurtherTo explore the link between alcohol problems and deviant child behavior in parents of children with ADHD, As in the studies by Despite the increased distress levels, however, parents of ADHD children as a group did not display the stress-induced drinking shown by college students or parents of normal children. Deviant child behavior resulted in elevated drinking levels only when the investigators conducted the subgroup analyses based on family history of alcohol problems. Thus, parents with a positive family history of alcohol problems exhibited higher drinking levels after interacting with deviant children than after interacting with normal children. Conversely, parents without a family history of alcohol problems showed lower drinking levels after interacting with deviant children than after interacting with normal children.This finding was somewhat surprising, because the investigators had strongly expected parents of ADHD children as a group to exhibit elevated drinking in response to deviant child behavior. The study results suggest, however, that some parents of ADHD children  may have developed coping techniques other than drinking  to cope with the stressors associated with raising a child with deviant behavior. Consequently, it is important to measure additional differences among individuals in order to fully explain responses to various types of child behavior.Notably, the effect of a family history of alcohol problems on drinking levels was comparable for mothers and fathers. Most previous studies had demonstrated an association between a positive family history and alcohol problems in men, whereas the evidence for such an association in women was less convincing . FurtherTo facilitate data interpretation, the investigators modified the study design in several ways, as follows:They determined the subjects’ family histories of alcohol problems, defined as having a father with alcohol problems, prior to the study and used this information as a criterion for subject selection.They quantified stress-induced drinking for each subject using a within-subject design rather than the between-subject design employed in previous investigations. Thus, rather than comparing subjects who had interacted with a deviant child with subjects who had interacted with a normal child, the investigators had each subject participate in two laboratory sessions 1 week apart. In one session, the subject interacted with a deviant child and in the other session she interacted with a normal child.They measured the subjects’ heart rate and blood pressure during their interactions with the children in order to obtain physiological information about subjects’ stress levels.They administered numerous tests in order to identify dispositional characteristics, such as psychopathol-ogy, personality, coping, attributional style, alcohol expectancies, life events, family functioning, and drinking history, which might influence the subjects’ response in addition to the family history of alcohol problems.The results of the study confirmed the previous findings on the effects of child behavior on parental stress levels that were obtained from college students and parents of normal children. After interacting with the deviant children, the mothers of ADHD children showed greater physiological distress  than after interacting with the normal children. These mothers also showed greater subjective distress . Furthermore, the mothers consumed approximately 20 percent more alcohol after interacting with the deviant children than after interacting with the normal children a.These findings clearly demonstrate that interactions with ADHD children engender large stress responses from their mothers in multiple domains. Furthermore, the mothers in this study as a group coped with this distress by drinking more alcohol. Contrary to the family history analysis in the previous study , howeverTo further clarify the results of the study among mothers of ADHD children, the researchers also evaluated the mothers’ dispositional characteristics before their interactions with the children to identify potential associations with their stress-induced drinking b. The inHigher levels of routine drinking More negative consequences of drinkingHigher levels of drinking problemsA denser family history of alcohol problems Maternal history of drinking problemsHigher self-ratings of using mal-adaptive coping strategies, feeling depressed, and experiencing more daily life stressors.Although many mothers of ADHD children showed elevated drinking levels in response to interacting with a deviant child, a substantial number of mothers decreased their alcohol consumption after such interactions. This pattern of divergent responses is comparable to the one observed among mothers of ADHD children in the earlier study by The individual differences in coping with deviant child behavior noted in both studies suggest that alcohol consumption in mothers of ADHD children is a complex phenomenon. Clearly, some mothers resort to maladaptive coping mechanisms  in response to the stress of dealing with their child. Such a dysfunctional coping response often can be predicted by the mothers’ general coping styles. Other mothers, however, cope in a problem-solving fashion by decreasing their alcohol consumption when anticipating another interaction with the deviant child, apparently believing that drinking would decrease their effectiveness in interacting with that child.Whereas a paternal history of alcohol problems did not predict stress-induced drinking in the mothers of ADHD children, a maternal history of alcohol problems and the frequency of alcohol problems in other first-degree relatives did predict stress-induced drinking. These findings suggest that in addition to, or instead of, paternal alcohol problems, researchers should consider maternal drinking history and family density of drinking when assessing the influence of family history on female drinking behavior.The study on the mothers of ADHD children, as well as all the other studies in this series, was conducted in an “artificial” laboratory setting. The fact that subjects’ self-reported drinking levels  and self-reported alcohol problems correlated highly with stress-induced drinking measured in this setting confirms that this type of investigation can generate information that reflects real-life behavior.A recent review of the relationship between AOD abuse and parenting concluded that huge gaps exist in understanding the association between parental alcohol abuse and parent-child relationships . For exaChildhood externalizing disorders affect approximately 7.5 to 10 percent of all children, with a considerably higher incidence among boys. The association between childhood behavior disorders and parental alcohol problems means that many adults with drinking problems are parents of children with behavior problems. Moreover, the study by


This review article provides an overview of recent developments in antimicrobial peptides (AMPs), summarizing structural diversity, potential new applications, activity targets and microbial killing responses in general. The use of artificial and natural AMPs as templates for rational design of peptidomimetics are also discussed and some strategies are put forward to curtail cytotoxic effects against eukaryotic cells. Considering the heat-resistant nature, chemical and proteolytic stability of AMPs, we attempt to summarize their molecular targets, examine how these macromolecules may contribute to potential environmental risks vis-à-vis the activities of the peptides. We further point out the evolutional characteristics of the macromolecules and indicate how they can be useful in designing target-specific peptides. Methods are suggested that may help to assess toxic mechanisms of AMPs and possible solutions are discussed to promote the development and application of AMPs in medicine. Even if there is wide exposure to the environment like in the hospital settings, AMPs may instead contribute to prevent healthcare-associated infections so long as ecotoxicological aspects are considered. There are many classes of natural compounds, five of which are prevalent in natural product research today, namely: polyketides, alkaloids, terpenoids, ribosomal and non-ribosomal peptides , the latThe fundamental differences that exist between single-cell and multicellular organisms allow them to be targeted differently by AMPs. Some exhibit activities against wide variety of targets such as viruses, bacteria and fungi ,3,4. OthEarly studies generally considered the bacterial cytoplasmic membrane as a unique target for AMPs but within the last two decades several reports describing alternative mechanisms of action exist ,11,12,13Several approaches have been proposed and are currently utilized to improve these challenges created by the intrinsic properties of AMPs ,29,30,31Remarkably, some AMPs have structural similarities to well-known toxins like the spider neurotoxin named Cm38 and Cn11, producing considerable toxicity to mammalian cells by themselves ,37,38. IGenome sequencing and transcriptomic data show that AMPs are ubiquitous in nature, and present in almost all living organisms ,41,42,43Echinus esculentus [Echinopsis pachanoi [AMPs from plants and animal sources have enormous structural diversity including those described earlier  56], as, as56], culentus  and EPrApachanoi  , but they possess an amphipathic structure that is a common feature to all of them. This feature enables them to bind and interact at the lipid bilayer membrane interface. The fact that most of these peptides interact with the lipid bilayer membranes is particularly concerning since such disturbance on the membranes may weaken their strength and render the cells more prone to lysis. Moreover, some AMPs (mostly from plants and insects) have the ability to penetrate the membrane and interact with intracellular processes and as such, this must be kept in mind when modifying or designing a new molecule to ensure its relevance and safety.AMPs produced by bacteria are generally called ribosomal or non-ribosomal peptides based on their biosynthesis mechanism. Those that are ribosomally synthesized are generally referred to as bacteriocins. Bacteriocins are defined as “a group of proteinaceous substances produced at ribosomal level, having multifunctional properties whose antimicrobial activities are concentration-dependent ”. This dStreptomyces sviceus -2-deoxy-d-glucose (2-NBDG) to measure sugar transport across the cell membrane.Sugar transport across the cell membrane may be assessed using rudimentary approaches that measure sugars uptake by cells. Flow cytometry or fluorimetry or liquid scintillation counting may be used in conjunction with a fluorescent sugar analogue like the 2-[The ToxTracker assay  which haE. coli DnaK [Apidaecin, pyrrhocoricin and drosocin are PrAMPs that displayed defined interactions with oli DnaK . Howeveroli DnaK , indicatoli DnaK . Since a(1–35), and other insect-derived PrAMPs were shown to bind or interact with 70S ribosomes [Bac7ibosomes ,144 whilibosomes ,146. In ibosomes . Inhibit® have encouraging records, there is no doubt that AMPs face a lot of developmental challenges ranging from production to clinical development. These obstacles are conflicting with the numerous academic publications that appear every year to argue the potentials of these biomolecules as alternative drug targets. Perhaps better understanding of the mode of action, target molecules or complex, and mechanism of host protection may further improve the current situation and reduce time and capital investments which may be frustrating at best in the event of an unsuccessful venture. The solution to these challenges must be multifaceted in nature. This may include, amongst others, utilizing natural AMPs as backbones in rational semisynthetic desins to improve their therapeutic qualities and engineering the peptides to reduce toxicity to host cells, or increase their activities.Several screening methods have enabled isolation and characterization of novel antimicrobial peptides both from natural and synthetic sources. Special features are required in the peptides for them to perform the desired functions, provide resilience and target specificities that make them therapeutically interesting. Although the market situation for AMPs like Bacitracin, Polymyxin and FuzeonMembrane interactive models like the toroidal pore formation, carpet and barrel-stave pore have allowed the possibilities to evaluate how AMPs affect bacteria based on their conformational flexibilities and nature of the lipids in the bilayer and thus, understanding the molecular interconnectivities of the peptide-target interactions may greatly facilitate the creation of new molecules using the current ones as templates. Analysing the molecular bases of targeting intracellular components is also important to identify the types and nature of interactions involved, which may provide information on how to develop peptides with superior potencies and the propensity to escape bacterial resistances. Meanwhile suboptimal structural arrangement in the peptides may result in drastic decrease in activity, it may be useful to design peptides that are more target-specific to make them safe for human consumption and ecofriendly to other organisms.Nevertheless, natural AMPs show high potency against pathogenic microbes, targeting multiple cellular macromolecular structures whose constituent building blocks or conformational dynamics vary from species to species and therefore, resistance development is rare. As such, even if there is wide exposure to the environment like in the hospital settings, AMPs may instead contribute to prevent healthcare-associated infections in hospital settings and food-borne illnesses so long as environmentally friendly species are not targeted.


To investigate the effect of endocrine therapies on a wide range of specific clinical cardiovascular disease outcomes in women with a history of non-metastatic breast cancer.Systematic review and meta-analysis of randomised controlled trials and observational studies.Medline and Embase up until June 2018.Studies were included if they investigated the risk of a specific cardiovascular disease outcome associated with use of either tamoxifen or an aromatase inhibitor, or compared the two treatments, in women with a history of non-metastatic breast cancer.Relevant studies were originally identified and results extracted by one researcher, with a full replication of the study identification process by a combination of two other researchers. The Cochrane Collaboration’s tool for assessing risk of bias was used to assess risk of bias in randomised controlled trials, and this tool was adapted to assess risk of bias in observational studies.26 studies were identified, with results for seven specific cardiovascular disease outcomes . Results suggested an increased risk of venous thromboembolism in tamoxifen users compared with both non-users and aromatase inhibitor users. Results were also consistent with a higher risk of the vascular diseases myocardial infarction and angina in aromatase inhibitor users compared with tamoxifen users, but there was also a suggestion that this may be partly driven by a protective effect of tamoxifen on these outcomes. Data were limited, and evidence was generally inconsistent for all other cardiovascular disease outcomes.This review has collated substantial randomised controlled trial and observational evidence on the effect of endocrine therapies on several specific cardiovascular disease outcomes including venous thromboembolism and myocardial infarction, progressing knowledge. Although the choice of aromatase inhibitor or tamoxifen will primarily be based on the effectiveness against the recurrence of breast cancer, this review shows that the individual patient’s risk of venous or arterial vascular disease should be an important secondary consideration.Prospero CRD42017065944. Endocrine therapies—namely, tamoxifen and aromatase inhibitors—reduce the risk of reoccurrence of breast cancer in patients diagnosed as having oestrogen receptor and/or progesterone receptor positive breast cancer following surgery (adjuvant treatment). The efficacy of tamoxifen, irrespective of menopausal status, has been confirmed in several randomised controlled trials,Several systematic reviews and meta-analyses of randomised controlled trials,The aims of this systematic review were to identify and summarise both randomised controlled trial and observational evidence on associations between endocrine therapies and a wide range of specific clinical cardiovascular disease outcomes in women with a history of early breast cancer, to describe the differences between findings from randomised controlled trials and real world observational studies, and to assess the quality and potential for bias in studies investigating this topic.We included randomised controlled trials and observational studies if they carried out at least one analysis assessing the risk of a specific cardiovascular disease outcome associated with tamoxifen, aromatase inhibitors, or a comparison of the two treatments after the diagnosis of non-metastatic breast cancer in women. The outcomes of interest were vascular disease—angina, myocardial infarction, revascularisation procedures, sudden cardiac arrest, stroke (haemorrhagic and ischaemic), and peripheral vascular disease; myocardial disease—cardiomyopathy, heart failure, and arrhythmia; venous thromboembolism; pericarditis; and valvular heart disease.We excluded studies if only a composite cardiovascular disease outcome or mortality from cardiovascular disease was assessed, only women with metastatic breast cancer were included in the study population, or the study exclusively analysed temporal differences for the same treatment on the risk of cardiovascular disease. We also excluded previous systematic reviews and meta-analyses exploring the cardiotoxicities of systemic breast cancer therapies , but we included relevant randomised controlled trials captured in these reviews that were not captured in the main search, along with any more recent or previously unidentified trials. We also manually searched all randomised controlled trials of endocrine therapy for breast cancer published since the most recent systematic review to ensure that more recent trial papers were not missed.We used the health and medical literature databases Medline and Embase to search for relevant publications. The searches were performed in June 2018. Conference abstracts, grey literature, and unpublished studies were not included. To identify all relevant literature, the search strategy for each database included a comprehensive list of both index and free text terms for breast cancer, endocrine therapies, and cardiovascular disease. The full search terms used are outlined in appendix 2. We manually searched the reference lists of all studies identified in the search to further identify relevant studies that were originally missed.We extracted relative risks, odds ratios, or hazard ratios if they were calculated in the paper. We calculated the relative risk and 95% confidence interval if effect estimates were not presented but data on the number of outcome events in follow-up allowed their calculation. We also collated information on the country in which the study was based, study type , data source , study design , age of included patients, inclusion criteria, exclusion criteria, intervention arm (and number of patients in the arm), reference arm (and number of patients in the arm), primary endpoint, cardiovascular disease outcome(s) assessed, mean/median follow-up time, statistical methods, and covariates adjusted for.One researcher (AM) identified all relevant studies from the original literature search and extracted the results of these studies. The study identification process was repeated by a combination of two other authors (RF and HS). The extraction table was also piloted on two studies by two researchers (AM and RF) to check reproducibility of key information.We used the Cochrane Collaboration’s tool for assessing risk of bias to assess risk of bias in randomised controlled trials.We organised seven possible comparisons between study arms/exposures during follow-up into three groups defined a priori to aid presentation. Group 1 included the direct comparison between aromatase inhibitor use and tamoxifen use during follow-up. Group 2 included three comparisons, all characterised as addition of tamoxifen in the intervention arm during follow-up  versus aromatase inhibitor). Group 3 also included three comparisons, with addition of aromatase inhibitor in the intervention arm during follow-up .2 tests and P values for Cochrane Q tests to assess heterogeneity.2 value of above 25% to be evidence of between study heterogeneity.To investigate differences in study findings for the same cardiovascular disease outcome, study type , and comparison (for the seven possible comparisons outlined above), we used INo patients were involved in setting the research question or the outcome choices, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results.The most commonly investigated outcomes were venous thromboembolism (n=15), myocardial infarction (n=14), and stroke (n=12). Arrhythmia and peripheral vascular disease were each investigated in a single study. Studied outcomes did not include revascularisation, sudden cardiac arrest, cardiomyopathy, pericarditis, or valvular heart disease.All observational studies had at least one domain categorised as being at high risk of bias. Six out of the 11 studies had a high risk of bias for the methods used to define exposure, which was mostly owing to not requiring women to have a minimum exposure period or several prescriptions before being categorised as exposed, raising the possibility of exposure misclassification. Risk of bias due to residual confounding was also present across both cohort and case-control observational studies. Seven studies adjusted only for basic risk factors and did not consider cardiovascular disease related treatment, cancer severity at diagnosis, or other cancer treatments such as chemotherapy or biological therapy.We did not assess publication bias because no cardiovascular disease outcome, study type, or comparison strata included more than 10 studies.2=0; Cochrane T test P=0.33; appendix 8),2=0%, Cochrane Q test P=0.70, 2=45%; Cochrane Q test P=0.16).2=92%, Cochrane Q test P=0.00).Among 26 studies providing data on seven specific cardiovascular disease outcomes, we found consistent evidence of an increased risk of venous thromboembolism in tamoxifen users compared with non-users in both randomised controlled trials and observational studies, with a correspondingly decreased risk of venous thromboembolism when aromatase inhibitor users were compared directly with tamoxifen users. However, the direct effect of aromatase inhibitors on venous thromboembolism was less clear, as only a single randomised controlled trial compared aromatase inhibitor with placebo, finding an increased risk in aromatase inhibitor users. The evidence on the effects of endocrine therapies on vascular disease risks was mixed: most studies were consistent with a higher risk of myocardial infarction and angina in aromatase inhibitor users compared with tamoxifen users, and there was a suggestion that this may be partly driven by a protective effect of tamoxifen on these outcomes; inconsistent results were found for the associations with stroke. Of the few studies assessing other outcomes, data were limited and very mixed patterns were observed, making drawing conclusions difficult.Thirteen of the 15 randomised controlled trials identified disease-free survival as the primary outcome of the study, whereas all observational studies identified either one or several specific cardiovascular disease events as their primary outcome. Women with previous cardiovascular disease were therefore excluded from many observational studies but not from randomised controlled trials. Overall, women included in the randomised controlled trial populations were therefore likely to be at a higher absolute risk of cardiovascular disease during follow-up, which would be problematic only if the prevalence of cardiovascular disease at baseline was different between the treatment arms. In theory, randomisation should result in an equal prevalence of cardiovascular disease at baseline between arms. However, many included studies did not report information on randomisation and concealment of allocation, meaning that selection bias in relation to prevalent cardiovascular disease at the point of randomisation cannot be disregarded. Randomised controlled trials also did not report data on cardiovascular disease risk at baseline, but participants in trials are likely to be healthier than the general population and thus may have had less previous cardiovascular disease. As people with previous cardiovascular disease are likely to be underrepresented in randomised controlled trials, and are excluded from observational studies, the evidence on the association between endocrine therapies and risk of cardiovascular disease in this population remains limited. Furthermore, as the randomised controlled trials were mainly designed to assess disease-free survival, they were not always adequately powered to detect relative differences in the risk of clinical cardiovascular disease outcomes between treatment arms.Definitions of cardiovascular disease outcomes were generally poorly recorded in the included studies. Between study variation could therefore exist in the measurement or coding of cardiovascular disease outcomes. Most oncology trials use the CTCAE criteria for adverse events, which have definitions that do not align with definitions in cardiology guidelines, although even the latter have variability. Furthermore, as observational studies rely on definitions of outcomes suggested by researchers and clinicians, differences in coding of outcomes could be a further source of heterogeneity in the observational studies. Without access to the outcome definitions and code lists used in these studies, fully understanding the extent to which the differences are problematic is challenging.A biological rationale exists for the use of aromatase inhibitors increasing the risk of cardiovascular disease outcomes, as they reduce oestrogen concentrations and therefore the oestrogen-mediated protective effects on cardiovascular disease, such as regulation of serum lipid metabolism, increasing vasodilation, and inhibition of the development of atherosclerosis.We found evidence of heterogeneity between all four strata of observational studies exploring the same exposure and outcome , which was potentially driven by the differences in study populations, statistical techniques used, and covariates adjusted for (appendix 5). For example, one cohort and one case-control study reported an increased risk of venous thromboembolism in tamoxifen users compared with non-tamoxifen users in European study populations , whereas a study in Taiwan reported no evidence of a difference in risk. More broadly, as this systematic review attempted to cover a wide range of clinical cardiovascular disease outcomes, some included observational studies focused on one cardiovascular disease outcome, whereas others covered a broad range of cardiovascular disease outcomes. Different statistical techniques and covariate adjustments were therefore needed. The effect of this heterogeneity between studies was witnessed in the varying relative risks reported within these strata of observational studies, which could be either a product of genuine discrepancies in risks between contrasting populations or the effect of residual confounding and different statistical techniques.The addition of observational studies in this review allowed comparison of results between real world populations and randomised controlled trials that generally use homogeneous study populations. Overall, we mostly found agreement in the direction of effect between randomised controlled trials and observational studies, but several observational studies reported more extreme effect estimates in comparison with randomised controlled trials . However, these observational studies all had a high risk of bias in at least two assessment of bias categories. Including observational studies also enabled further evidence to be gathered where little or no evidence from randomised controlled trials existed. For example, we identified six observational analyses of vascular endpoints finding good or strong evidence for a higher risk for aromatase inhibitor compared with tamoxifen or a lower risk for tamoxifen compared with no tamoxifen. Most randomised controlled trial analyses were underpowered to detect differences in vascular endpoints, with only three finding similar clear evidence despite several others being suggestive of associations in the same direction.We grouped comparisons on the basis of the drug women were given at the beginning of follow-up. For example, in several randomised controlled trials, women were given two to three years of tamoxifen before being randomised to either aromatase inhibitor or the continuation of tamoxifen for a further two to three years, with follow-up beginning at the point of randomisation. We classed these as a direct comparison of aromatase inhibitor versus tamoxifen, whereas previous reviews classed these comparisons as sequenced therapy versus tamoxifen alone. As all women had had the same treatment regimen before randomisation, classing these as aromatase inhibitor versus tamoxifen was a reasonable comparison to make.The most recent meta-analysis by Khosrow concluded that randomised controlled trials directly comparing aromatase inhibitors with tamoxifen suggest that aromatase inhibitors are associated with an increased risk of cardiovascular events, but the cardioprotective effects of tamoxifen may account for this increased risk.This study focused on individual clinical cardiovascular disease outcomes, excluding studies that reported composite outcomes. Understanding the effect of endocrine therapies on cardiovascular disease as a whole has several advantages, such as the potential to change the modifiable risk factors weight, smoking, statin use, and alcohol intake, which are present across all clinical cardiovascular diseases. However, understanding the effect of endocrine therapies on more specific clinical cardiovascular disease outcomes has the potential to enable clinicians to be targeted in their approach to preventing these outcomes in breast cancer survivors. The only composite outcome that we explored was venous thromboembolism, as some studies in this group included only deep vein thrombosis outcomes whereas others also included pulmonary embolism within a venous thromboembolism outcome. However, this grouping is relevant owing to the clinical similarities of deep vein thrombosis and pulmonary embolism.Some relevant studies may have been missed, as searches of literature database take into account only indexed key terms or words used in the title and abstract. Studies in which the secondary outcome was a cardiovascular disease would therefore not have been identified in the original search. For example, several randomised controlled trials that focused on anticancer efficacy do not mention cardiovascular diseases in the title, abstract, or indexed keywords. However, we searched multiple large databases, manually searched the included studies’ reference lists and relevant meta-analyses, and searched all endocrine therapy trials since the most recent meta-analysis, which was an indirect way of identifying the aforementioned randomised controlled trials and made this review as comprehensive as possible within the restricted framework imposed by the literature databases.This review establishes the need for clinical vigilance and possible preventive measures when prescribing endocrine therapies to women at risk of venous thromboembolism. Knowledge has also been progressed on the effects of endocrine therapies on the risk of vascular cardiovascular diseases, for which little evidence previously existed. However, we also showed that little or no evidence is available on the effect of endocrine therapies on several other specific cardiovascular disease outcomes, although substantial trial evidence outlines the effect on cardiovascular diseases generally. This is unlikely to be studied in future randomised controlled trials, so it is vital that large observational studies are carried out with details of baseline cardiovascular disease risk and drug treatment and clear definitions of cardiovascular disease events to fully understand the effects that endocrine therapies have on potentially fatal cardiovascular disease outcomes such as myocardial infarction, stroke, and heart failure.Overall, the totality of the randomised controlled trial and observational evidence suggests a decreased risk of venous thromboembolism in aromatase inhibitor users compared with tamoxifen users, which is probably accounted for by an increased risk in tamoxifen users. The evidence also suggests that tamoxifen may have a protective association with vascular cardiovascular diseases, which may drive the higher risk of these outcomes in aromatase inhibitor users when directly compared with tamoxifen users. The results for some cardiovascular disease outcomes is still a mixed picture, many of the existing studies are susceptible to various sources of bias, and cardiovascular disease outcomes collected in oncology trials are generally limited. Nevertheless, the addition of observational studies alongside randomised controlled trials has substantially increased the amount of evidence supporting these conclusions. However, further high quality evidence is still needed for several cardiovascular disease outcomes. Although choice of aromatase inhibitor or tamoxifen will primarily be based on the effectiveness against recurrence of breast cancer, the individual patient’s risk of venous or arterial vascular disease is an important secondary consideration, and the totality of evidence we present will thus help to inform prescribing.Several meta-analyses of randomised controlled trials have reported the effect of endocrine therapies used in adjuvant treatment of breast cancer on the risk of composite cardiovascular disease outcomesHowever, these reviews have not reported the effect of endocrine therapies on a range of clinically specific cardiovascular diseasesThey have also omitted the growing body of evidence from observational studies, which often include large study populations in real world settings, as well as longer follow-upObservational evidence is generally consistent with trial evidence reporting an increased risk of venous thromboembolism in tamoxifen users compared with both non-users and aromatase inhibitor usersEvidence also exists of a higher risk of vascular disease in aromatase inhibitor users compared with tamoxifen users, which may be driven by a protective effect of tamoxifen


The intensive care unit (ICU) is an incredibly complex environment, and ICU rounds are mentally taxing. The cognitive biases that tend to arise in mentally taxing environments such as the ICU pose a risk to patients. This review discusses 10 common cognitive biases and logical fallacies using examples in Nephrology Critical Care. Our objective is to promote metacognition  among physicians. A state of metacognition is not a panacea, but aspiring for metacognition allows the critical care physician to improve chances for optimal patient outcomes. To conserve precious energy and to promote expediency, the mind creates mental short cuts called heuristics . HeuristTable Creatinine rise: post hoc fallacy The diagnosis of acute kidney injury (AKI) based on KDIGO  criteria is dependent on an increase in serum creatinine and reductions in urine output . HoweverHepatorenal syndrome: base rate fallacy AKI is a frequent complication of advanced cirrhosis, and hepatorenal syndrome (HRS) is an important differential to consider, but the diagnosis should be discussed with an understanding of its base rate. The primary mechanism for HRS is portal hypertension-related splanchnic vasodilatation with an associated drop in effective circulating volume. AKI with cirrhosis is often assumed to be HRS due to an overestimation of the base rate of HRS. HRS can be diagnosed only after ruling out alternative causes, including intravascular depletion, obstruction, medications, and glomerular disease. The diagnostic criteria for HRS include no improvement in renal function following two days of albumin infusions with complete withdrawal of all diuretics, the exclusion of nephrotoxic agents, and parenchymal renal disease . In an oAbdominal compartment syndrome: false dichotomization Intraabdominal hypertension (IAH) is defined by an intraabdominal pressure (IAP) of >12 mmHg, which occurs as a result of reduced abdominal compliance. Abdominal compartment syndrome (ACS) is diagnosed when the IAP is > 20 mmHg with concurrent end-organ dysfunction . Renal dNormal saline: status quo bias (the bias of opting for the familiar)Chloride in extracellular fluid is essential in the maintenance of osmolality, acid-base balance, and sodium regulation, but iatrogenic hyperchloremia can be detrimental. Normal saline is the most widely used fluid composition in medicine but has significantly higher chloride load as compared to serum. The evidence favors balanced chloride solutions. Multiple clinical trials have demonstrated that the use of chloride-rich crystalloid solutions is associated with increased risk of AKI and mortality , yet itsLactic acidosis: reduction fallacy Lactate production and clearance is a complicated process with many etiologies, but a rise is often met with a fluid bolus. Reflexive fluid administration in response to a lactate rise is an example of the reduction fallacy-the fallacy of reducing a multifaceted process to a single cause-in this case, hypoperfusion. It stands to reason that if lactate increase is a specific marker for volume depletion, volume should be the answer. But how accurate is it? The belief that hypoperfusion is a primary mechanism for lactate rises in sepsis has come under scrutiny. There are physiologic studies that question the perception that reduced oxygen delivery due to hypoperfusion in sepsis causes lactate rise . AdrenerFurosemide-related hypernatremia: the law of the instrument bias Furosemide is a diuretic that works at the loop of Henle and is typically used to achieve negative fluid balances in settings of organ congestion. Where diuresis is concerned, furosemide falls victim to the law of the instrument fallacy. Monotherapy loop diuretic strategy leads to more electrolyte reabsorption in the distal segments of the nephron, leading to more hypotonic urine, which predisposes the patient to hypernatremia. Hypernatremia is one of the more frequent electrolyte disturbances seen in the ICU , commonlShock precluding fluid removal: Semmelweis reflex bias (tendency to reject new evidence in the face of a known paradigm)Vasoactive medications  are used to treat poor tissue perfusion as indicated by low MAP, oliguria, and low capillary refill. Once vasoactive medicines are in use, particularly in cases of septic shock, the decreased MAP is thought to occur at least partially from hypovolemia . HoweverSepsis-related AKI: illusory truth effect (truth is what is repeated)There is a high incidence of sepsis-related AKI . Early vContrast-induced AKI: conservatism bias (inadequate revision of belief when presented with new evidence)Contrast-induced nephropathy (CIN) is defined as an increase in creatinine of 0.3 mg/dl within 48 to 72 hours to exposure . ImpliedVolume tolerance: automation bias Assessment of volume status is a crucial part of the evaluation of a critically ill patient. Both volume depletion and volume overload can lead to complications, but most algorithms  favor volume administration . PatientThe ICU is an extraordinarily complex environment which can be cognitively taxing for intensivists. When difficult decision making is frequent and sustained, intensivists are predisposed to cognitive biases which can lead to poor outcomes for patients. Addressing the problem of cognitive biases in ICU requires intellectual humility to recognize the fallibility of the human mind, paving the way for metacognition. We propose the use of metacognition in the ICU for a higher vantage point to view our errors in logic, which can only benefit our patients.


With rising health care costs, governments must develop innovative methods to deliver efficient and equitable health care services. With physician remuneration being the third largest health care expense, the design of remuneration methods is a priority in health care policy. Otolaryngology-Head and Neck surgeons should have an understanding of the behavioural incentives associated with different physician payment methods. This article will outline the different physician payment methods with a focus on discussing the impact on quality of care and health care costs. With rising health care (HC) costs and squeezed financing, governments must develop innovative methods to deliver efficient and equitable health care services. However, delivering efficient health care is inherently complex and relies on a stochastic process of evaluating disease probabilities and promoting desired behaviours by health care providers and patients.A recent article by Wranik evaluated twenty-one Organization for Economic Co-operation and Development (OECD) countries concluding that policies targeting patient behaviour and physician remuneration were significant contributors to the efficiency of health care delivery . CoupledIt is commonly accepted that payment methods influence physician practice behaviour . It is eThis article aims to provide Otolaryngologists with a basic overview of the theory behind behavioural incentives associated with different physician payment methods and highlight the empirical evidence that supports or contradicts theoretical claims. We argue that evidence is not sufficiently strong which has served as the impetus behind the changes in physician remuneration introduced in Canada.The three pure physician payment methods include: fee-for-service (FFS), capitation, and salary. Since each have strengths and weaknesses, many jurisdictions have implemented blends of the three systems to combine the strengths and counteract the weaknesses. In addition, several jurisdictions have introduced various forms of pay-for-performance (P4P) systems in an attempt to improve HC quality through payment mechanisms.When discussing a health care intervention, such as physician remuneration, defining the term ‘quality’ can be challenging since it often depends on perspective. A patient may define quality in terms of wait-list times, equity of access, continuity of care, or visit satisfaction. From a physician’s perspective, quality may refer to patient outcomes , professional autonomy, or practice satisfaction. From the health system perspective, quality may signify appropriateness of services provided and budget control. For the purposes of this article, quality will be discussed in terms of patient satisfaction, appropriateness of care, and continuity of care.The fee-for-service (FFS) system rewards the provider on a “per item of service provided” basis. Physician income is directly related to the number of health care services performed, creating an incentive to perform a high quantity of health care activities as financial risks associated with high volumes of activity sit with the payer. Since there is motivation to provide high amounts of services, it is in the physician’s interest to focus on patient satisfaction and therefore patient retention. The system also treats each patient equally creating equal incentives to accept high cost and/or low cost patients; a feature violated in a capitation or salary system. A FFS system is typically coupled with a provider-owned solo or group practice, which offers flexibility, autonomy and entrepreneurial opportunity.A Swedish study by Forsberg et al. demonstrated that physicians are more aware of patient satisfaction when receiving FFS remuneration . An AmerDevlin and Sarma propose that FFS remuneration tends to increase health care expenditure, primarily attributed to a greater quantity of care provided by physicians and higher administrative costs . An impoWhen the goals of a health care system are to increase patient satisfaction, quantity of care provided, and reduce the likelihood of selecting low risk patients (i.e. cream skimming), then FFS appears to be an excellent remuneration method. FFS is, however, likely to increase costs due to a greater quantity of services provided but disentangling whether volume increases are due to productivity gains or SID deserves further empirical scrutiny.Capitation offers a “payment per patient per time period”. The incentive is to increase the clinical practice’s number of patients with no direct incentive to increase the quantity of health care activities provided. Therefore, the motivation is to accept relatively healthy patients, and reject (cream-skimming) or refer out (dumping) the relatively less healthy patients, since they will require a higher quantity of HC provided. For the payer, capitation is advantageous as providers face financial risks at the practice level.A Norwegian study by Iversen and Luras demonstrated that when remuneration changed from FFS to capitation-based payment, physicians increased the referral of patients to private clinics for services that could have been provided by the referring physician . In 2009Proponents of capitation argue that it controls costs by eliminating the incentive for SID and increasing disease prevention and health promotion . The eviSalary is a fixed payment “per period of time” remuneration method. Therefore, payment is not dependent on the number of health care activities nor the number of patients. This payment method creates a stable, predictable income source for physicians, but also provides the incentive to reduce quantity of care. Salaries are an excellent method to recruit and retain physicians to under-populated or under-supplied regions, whereas FFS or capitation-based systems would inadequately reward physician efforts . SalarieProponents of salary-based physician remuneration state that it improves quality of care by increasing disease prevention, health promotion, and professional collaboration. A Canadian study by Battista and Spitzer demonstrated that salaried physicians performed more mammograms, fecal occult blood tests, and Pap-smears than FFS physicians . A UniteSalary payment methods are believed to control costs by minimizing SID and promoting increased appropriateness of care. Furthermore, fixed payments tend to lower administrative costs to the health care system. Despite these cost advantages, there is a risk that salary may come with societal opportunity costs by reducing productivity and under-providing appropriate care.There is increasing interest in blended physician remuneration, which combines the advantages from each method while minimizing the potential for negative behavioural incentives . A recenIt is still early to determine the full effects of blended payment methods on general practice. Combining a capitation method with FFS may increase health promotion and disease prevention, while maintaining productivity and patient access equality. Lower-density or undersupplied regions may benefit from a salary method combined with FFS, which increases physician recruitment and retention, while providing a financial incentive to maintain productivity. Future research is required to fully elucidate the effects of blended payment methods on quality and cost.With the objective to improve the quality of health care delivery as well as efficient delivery of care, pay-for-performance (P4P) both remunerates and measures physician performance based on achieving certain clinical targets at the patient population level and quality goals. Although P4P is appealing in theory, policy makers continue to face challenges identifying and implementing the ideal P4P structure that appropriately motivates physicians . DefininConflicting evidence on P4P highlights the complexity of this remuneration method’s design. When evaluating P4P in a PCP practice setting, a UK study by Doran et al. demonstrated accelerated quality improvements during the initial roll-out phases and failed to demonstrate a detrimental effect on non-rewarded clinical care sectors . SimilarIn order to align behavioural incentives with HC objectives without contributing to excessive increases in HC costs, there is an interest in developing novel physician remuneration methods in Canada. In the early years of implementing alternate payment plans (APPs) for physicians in Canada, several stakeholders thought APPs were going to replace FFS. However, in a 2011 report published by the Canadian Institute for Health Information (CIHI), the implementation of APPs  occurred by adding them to an existing FFS payment scheme. The addition of APPs to FFS increased by 3.6% suggesting that APPs are primarily being used to augment behaviours such as prevention and health promotion while keeping FFS to maintain volume of care ,25]. Ta. Ta25]. The challenge is that the implementation of APPs in Canada has typically been introduced to augment specialties with lower-than-average FFS incomes or remunerate physicians in low population regions. This has effectively increased the cost of physician remuneration when shifting from a pure FFS method. For example, in British Columbia the cost of changing from FFS to APP service contracts in the emergency department resulted in a cost increase of $12.8 million for service contacts . AnotherThe theory behind physician remuneration methods has been highlighted in many studies. We understand that in principle, FFS motivates quantity of care, while capitation motivates acceptance of healthier patients. Salaries offer stable incomes and allow physicians to focus their practice on patient needs, rather than on billable services. In theory, the blending of payment methods can combine the advantages of the pure methods. Where blending of methods is not sufficient, bonus pay-for-performance programs may be able to motivate the provision of targeted services. Policy makers need to consider not only the expected behavioural incentives associated with payment methods but also empirical investigation of these theoretical predictions.