Protein-protein interactions (PPIs) underlie the majority of biological processes, signaling, and disease. Approaches to modulate PPIs with small molecules have therefore attracted increasing interest over the past decade. However, there are a number of challenges inherent in developing small-molecule PPI inhibitors that have prevented these approaches from reaching their full potential. From target validation to small-molecule screening and lead optimization, identifying therapeutically relevant PPIs that can be successfully modulated by small molecules is not a simple task. Following the recent review by Arkin et al., which summarized the lessons learnt from prior successes, we focus in this article on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them. We conclude by providing a perspective on the field and outlining four innovations that we see as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.  •Limited surface contact reduces the druggability of PPIs•Structural plasticity confounds structural approaches•Complexity of biological networks defies rational target selection•Smarter target selection and more publicly available data will benefit future efforts Protein-protein interactions (PPIs) mediate numerous biological processes. This makes finding small molecules that target PPIs of high interest. However, finding such small molecules continues to be a challenge. Laraia et al. review the specific challenges of developing PPI inhibitors and highlight four innovations they consider critical to overcome these challenges. Protein-protein interactions (PPIs) have long been recognized as the key regulators of cellular pathways and networks. Developing tools to probe these interactions has led to an increased understanding of biological systems, and PPIs have also been targeted for drug development, due to the potential for selectively interfering with specific cellular pathways . Indeed,Although most approved PPI inhibitors currently find application as treatments for cancer or in regulation of the immune system, therapeutics targeting infectious diseases such as HIV have also been approved. With a greater understanding of the cellular pathways in different organisms will come an increase in the ability of PPI inhibitors to target infectious diseases. At the same time, the availability of patient-specific and tumor-specific data from high-throughput genome sequencing will enhance the potential of PPI inhibitors for targeting cancer. Prior to the early 1990s, PPI inhibitors were primarily identified through phenotypic screening, consistent with drug discovery approaches at the time. From the more recent examples, it is interesting to note that clinical candidates were originally identified using a wide variety of different in vitro approaches, including radioligand binding assays, fluorescence-based assays, fragment-based drug discovery (FBDD), and peptide mimic approaches. This observation suggests that PPI drug targets should be approached using several experimental methods, to maximize the probability of finding promising small-molecule leads. Exploiting multiple approaches is important because different kinds of PPI exhibit significantly different structural characteristics and present different challenges. For example, inhibitors required to mimic linear protein sequences (such as integrin inhibitors) have proved more successful than inhibitors required to mimic single regions of secondary structure (such as α-helix or β-hairpin mimics), which in turn have proved more successful than inhibitors required to mimic discontinuous binding epitopes derived from tertiary structures . In addiThe pharmaceutical industry has successfully developed drugs targeting only a small fraction of the components in the cellular signaling pathways that are misregulated in disease. Recent analysis of drug discovery efforts reveals that of the 15,000–20,000 genes encoded by the human genome, less than 300 have been specifically targeted with small molecules . More imCompared with the highly conserved nature of substrate binding pockets in enzyme classes such as kinases, PPI interfaces are inherently more diverse. For this reason, commentators have long postulated that PPI inhibitors will offer increased selectivity compared with existing small molecules. Maximizing target selectivity, of course, reduces the likelihood of off-target toxicities. In the well-publicized case of ATP-competitive kinase inhibitors, it is now an essential component of any assay cascade to rapidly ascertain the level of selectivity at target compared with the remainder of the kinome, by comparison against a panel of kinases . While mClinical resistance to substrate-competitive enzyme inhibitors occurs through the selection of mutant enzymes in which inhibitor binding is prevented by the alteration of non-essential structural features that contribute to binding affinity, without affecting the ability of the enzyme to bind to its natural substrate. In contrast to the evolutionary conservation of enzyme active sites, the structural features that underlie PPIs are often quite distinct, even between closely related enzymes, in enabling their specific cellular functions. These diverse structural features would seem likely to make resistance mutations that decrease inhibitor binding without perturbing the natural substrate less frequent. Therefore, in principle, targeting the PPIs that underlie protein function offers an attractive alternative to active-site inhibition of enzymes. Combining ATP-competitive kinase inhibitors with allosteric inhibitors of the same target to stall or even prevent the emergence of resistance is a novel concept in cancer drug discovery. Recent studies from Novartis have supported this concept, at least in a pre-clinical setting . In theshttp://www.thesgc.org/chemical-probes). Among these reported probes, PPI modulators of the BET bromodomains have been used to study their biological function and potential as anti-cancer therapeutics  have made optimized compounds publicly available as probe compounds. In the case of the SGC, these follow stringent criteria making them suitable for effectively studying protein function: on-target potency must be better than 100 nM, selectivity must be at least 30-fold, while cellular potency must be better than 1 μM , it can be an advantage in terms of pharmacokinetic/pharmacodynamic (PK/PD) control. An inhibitor that is buried in a binding site is likely to have the majority of its surface in close contact with the protein and, thus, very little of its surface available for chemical elaboration. Conversely, a PPI inhibitor that is half exposed to solvent has a much greater scope for chemical elaboration. This allows key physical properties such as the octanol/water partition coefficient (LogP) and polar surface area to be tailored without adversely affecting the binding affinity. This scenario has been exploited by Abbott for the development of Bcl-2 inhibitors in the progression from ABT-737 to ABT-263, where solvent-exposed positions were modified to optimize the balance between oral exposure in animals and efficacy in human tumor cell lines . A similTherapeutic targets are either established on a case-by-case basis as a result of focused research efforts, often within academia, or are identified using unbiased screens that attempt to associate particular gene products with a specific cellular response or phenotype. In terms of focused research, recent efforts have been guided by studying PPI networks. Understanding such networks would allow for major advances in biology such as identifying synthetic lethal interactions, understanding modes of toxicity, and explaining the resilience of cellular networks to disruption ; these a6–107) that often preclude further progression  the compound and the number of heavy atoms it contains (HA), using The concept of druggability measures the suitability of a protein target or specific binding site for development of a small-molecule inhibitor. It is important to note that studying binding to the protein target in isolation does not consider PK/PD factors that influence druggability. Thus, bindability  or ligan50 of the compound and its cLogP, using Lipophilic ligand efficiency (LLE) is another effective metric to drive decision making in medicinal chemistry, due to the deleterious effects of high lipophilicity on outcomes in drug discovery. LLE is calculated from the pICL, IL-2, and HDM2 overlaid on the protein structure from the apo state. The changes in protein structure mean that large portions of the inhibitors protrude into the protein surface. There are also cases, such as Keap1  is often used in an attempt to enrich compound libraries for molecules with an increased likelihood of hitting a particular target. The two main methods used for VS are structure-based and ligand-based screening . StructuThere are a number of reasons why developing therapeutics to target PPIs is a challenging process. In general, high-affinity protein-ligand binding is a driver of drug efficacy and is one of the key goals in early-stage drug discovery. This high-affinity binding is derived from close contact at the protein-ligand interface, and at protein surfaces a significant proportion of the ligand is exposed to solvent rather than in contact with the protein. Thus, for a given level of binding affinity, PPI inhibitors tend to be larger than inhibitors of buried binding sites. An increase in size brings with it a greater risk of PK/PD liabilities that may lead to drug failure. For this reason, PPI targets are considered to be inherently less druggable than traditional targets. Additional difficulties arise from the confounding effect of surface flexibility on structure-based drug design, and the challenges of target selection due to the complexity of cellular networks. However, PPI inhibitors hold great promise for the generation of selective therapeutics for a variety of diseases if these difficulties can be overcome. For this reason, great efforts have been focused on devising novel chemical, biological, and computational tools to aid in the process of developing PPI inhibitors. These tools are described in this review. In the future, we see four key areas where advances in our understanding and increases in the utility of computational techniques will further the development of PPI inhibitors.To date, PPIs have been targeted only sporadically with small molecules, at least partly because existing RNAi technologies are unable to associate specific PPIs with specific cellular phenotypes. Indeed, knockdown of candidate targets with RNAi can often be uninformative, due to the simultaneous depletion of beneficial as well as disease-associated protein interfaces. Therefore, since the current state of the art for target identification and validation is unsuitable for the identification of protein interfaces, it is not surprising that few PPIs have been validated as prospective targets using current tools. The problem of target selection is an area where computational approaches to systems biology hold great promise . HoweverAcademic research can also prove useful in the related process of validating difficult drug targets such as PPIs. Pharmaceutical companies are naturally wary of the risks associated with developing PPI inhibitors, and this is particularly true for unvalidated protein targets. The process of target validation can be a lengthy process and requires a coordinated multidisciplinary approach. For this reason, large initiatives such as the NIH Accelerating Medicines Partnership, the Wellcome Trust Seeding Drug Discovery funding, and the UK Technology Strategy Board Biomedical Catalyst funding will be a key part of target validation in the future. Publicly available data on the therapeutic potential of targeting all relevant proteins in the human genome would greatly enhance decision-making processes. However, the breadth and heterogeneity of genetic data will require cleverly designed and well-maintained databases.Publicly available data will also enable the design of effective screening libraries for PPIs. The results of many PPI screens with many libraries, including those where no leads were ultimately identified, will provide valuable information on whether particular libraries will fare well against PPIs, and whether particular PPIs may not be amenable to small-molecule inhibition. Unfortunately, both academia and industry are reluctant to publish negative results, and positive results are often delayed due to patent issues. Even when screens with positive results are published, a reader will rarely have access to all compound structures and associated activities. Only with a complete dataset can a comprehensive analysis be carried out. We envisage that the current drive for “big data” will help to separate druggable and undruggable PPIs and validate effective screening libraries for PPIs.One area in the development of PPI inhibitors where experimental data may not prove as fruitful is the identification of cryptic binding pockets at protein surfaces. Such pockets are often druggable but are not identified by X-ray crystallography of the apo protein structure. Brute force experimental approaches using HTS or arrayed library synthesis can work but the vast size of chemical space means that such approaches will commonly fail. Conversely, computational methods can search the conformational space of the protein surface and identify the presence or absence of druggable pockets. The two barriers to achieving this are the two main issues that have always existed in computational drug discovery: sampling and scoring . SignifiIn summary, the development of effective therapeutics from PPI inhibitors will be improved by the widespread dissemination of relevant data from large multidisciplinary projects, the effective use of such data, and the exploitation of increased computing power to accurately model ensembles of protein structures. Science is already moving in these directions, but academia and industry will need to work together in order to turn this movement into positive outcomes for society.


Non-conscious neural activation may underlie various psychological functions in health and disorder. However, the neural substrates of non-conscious processing have not been entirely elucidated. Examining the differential effects of arousing stimuli that are consciously, versus unconsciously perceived will improve our knowledge of neural circuitry involved in non-conscious perception. Here we conduct preliminary analyses of neural activation in studies that have used both subliminal and supraliminal presentation of the same stimulus.We use Activation Likelihood Estimation (ALE) to examine functional Magnetic Resonance Imaging (fMRI) studies that uniquely present the same stimuli subliminally and supraliminally to healthy participants during functional magnetic resonance imaging (fMRI). We included a total of 193 foci from 9 studies representing subliminal stimulation and 315 foci from 10 studies representing supraliminal stimulation.The anterior cingulate cortex is significantly activated during both subliminal and supraliminal stimulus presentation. Subliminal stimuli are linked to significantly increased activation in the right fusiform gyrus and right insula. Supraliminal stimuli show significantly increased activation in the left rostral anterior cingulate.Non-conscious processing of arousing stimuli may involve primary visual areas and may also recruit the insula, a brain area involved in eventual interoceptive awareness. The anterior cingulate is perhaps a key brain region for the integration of conscious and non-conscious processing. These preliminary data provide candidate brain regions for further study in to the neural correlates of conscious experience.The online version of this article (doi:10.1186/s40359-014-0052-1) contains supplementary material, which is available to authorized users. Recent brain imaging evidence suggests that subliminal stimuli can alter behavior, via non-conscious processes  and Tranel (55) proposes that emotions, which help us to make decisions, are cognitive stories constructed by the cortex in a particular context to explain bodily arousal; a view reflected in their recently updated Somatic Marker Hypothesis, highlighting the importance of brainstem  activation in conscious experience Damasio . PerceptA recent qualitative review of subliminal findings in functional Magnetic Resonance Imaging (fMRI) research reports that non-consciously perceived stimuli can influence perceptual, lexical and semantic processing, but that the neural response to subliminal stimuli depends on the strength of stimulus presentation, as well as individual differences in threshold for conscious perception  stimuli evoke distinct activations in primary visual areas, somatosensory regions, implicit memory and conflict monitoring systems independent of conscious awareness of the stimulus  with the same participants and the same experimental conditions within the same publication. In all studies included, subliminal perception was confirmed by a forced choice task. This meta-analysis differs from our recently published meta-analysis where only fMRI studies using subliminal stimuli  were included with no activation to supraliminal perception  the study included a direct contrast between brain activation to subliminal and supraliminal stimulus presentation, d) were original articles written in English, e) used functional Magnetic Resonance Imaging (fMRI) and not other brain imaging modalities  so that the data could be better aggregated for meta-analysis, and f) reported the neural activation coordinates in Montreal Neurological Institute (MNI) or Talairach space  studies were published within the last decade, between January 2001 to October 2013, b) published in a peer-reviewed journal, c) used a task that utilized both the subliminal and supraliminal presentation of the We found 77 studies that were initially screened for inclusion in the systematic review, but 20 of these did not meet the eligibility criteria described above. Of these 57 eligible studies, 13 were not included in the meta-analyses because they did not provide details of Talairach or MNI peak activation coordinates, and we were not able to contact the authors. Of the 44 fMRI studies to date, only 16 of these explicitly analyzed contrasts between subliminal and supraliminal thresholds of the same arousing stimulus or analyzed subliminal/supraliminal stimulation with a methodology similar to the one used in studies implying direct comparison between two different kinds of stimulation . Of the 16 remaining studies with subliminal vs. supraliminal studies with some overlap in studies presenting both subliminal and supraliminal stimuli, 6 of these were excluded because they used exclusively Region of Interest (ROI) analysis, a technique that analyzes only a small region of the brain, based on a priori hypotheses. This is in contrast to a Whole Brain (WB) analysis, which statistically analyzes activation across the whole brain in one analysis. Thus, this left 10 WB fMRI studies that specifically included brain imaging coordinates for both subliminal and supraliminal perception, uniquely, of the same affective stimulus. It must be noted that one of the 10 studies directly compared subliminal with supraliminal presentation of the same stimulus, but only reported differential activation in the supraliminal condition, resulting in 9 studies contributing to the subliminal condition, and 10 studies contributing to the supraliminal condition. We included studies that either provided a direct comparison between subliminal versus supraliminal stimulation, or compared against a neutral condition . See Table FMRI studies included in this meta-analysis contrast neural activation to subliminal and supraliminal presentation of the same stimuli (see Table http://ric.uthscsa.edu/mango) to illustrate the results of our meta-analyses, using the Colin27_T1_seg_MNI template provided on the GingerALE website (http://www.brainmap.org). We also used the Colin27_T1_seg_MNI template to produce the schematic summary of our findings in Figure To examine relative activation to the subliminal and supraliminal presentation of arousing stimuli, we conducted two separate meta-analyses using BrainMap GingerALE version 2.3.1 software  in BA 19, cluster two was found in right caudal anterior cingulate cortex  in BA 32 and cluster three was found in right insula  in BA 13.From 320 foci, 188 subjects and 10 separate experiments, 2 significant clusters were found that survived the cluster level inference threshold. Cluster one was found in left anterior cingulate cortex  in BA 32, cluster two was found in mid-caudal anterior cingulate cortex  in BA 32.See Table For a schematic illustration of where these regions are in the brain, and possible connections, see Figure We present preliminary meta-analyses of fMRI studies that compare the effects of subliminal versus supraliminal presentation of the same stimulus on brain activation. When interpreting these findings, the categories and differences between visual and tactile stimulation must be considered with caution, as they may influence the data observed. Specifically, left anterior cingulate cortex (ACC) was most significantly activated across all studies when supraliminal processing was the reported activation; the right fusiform gyrus/middle occipital gyrus and right insula when subliminal processing was reported, and the caudal anterior cingulate cortex to both levels of perception. Additionally, it appears that subliminal stimulation most often activates regions of the right hemisphere, whereas in contrast, supraliminal stimulation appears to activate the left hemisphere. This is intriguing given that the right hemisphere is typically associated with emotional processing, whereas the left hemisphere is linked to language processing and higher level emotional processing that is largely consciously perceived  being activated to non-consciously presented stimuli, but instead found that the right fusiform gyrus and right insula cortices were most significantly activated by subliminal stimuli. However, again it must be considered that these observations could be due to the type of stimuli used , rather than as a consequence of variance in conscious perception. Most other fMRI studies using subliminal paradigms compare subliminal arousing to subliminal neutral stimuli, but the studies included in this review only compared supraliminal and subliminal presentation of the same stimulus within the same study , which is in agreement with our previous meta-analysis of fMRI studies  was observed across studies in response to both subliminal and supraliminal arousing stimuli in this review. This brain area is considered crucial in the detection of error following a false mental prediction and in the detection of internal conflict, such as dissonance between two competing goals, but it is unclear whether this is associated with conscious perception of the stimulation or not  in unconscious processing, but instead found that non-consciously processed stimuli activate visual cortex, insula and ACC. Against the background of the current data, must proceed with caution when choosing subliminal paradigms to test theories of unconscious perception, given our current lack of knowledge regarding the underlying mechanisms of subliminal stimulation. For example, it is not currently known to what extent the semantic context of masked stimuli is processed at an unconscious level, and whether subliminal stimulation activates processes that linger in the brain for secondary higher-order conscious processing. Given these limitations to our current knowledge, subliminal paradigms may not be the best choice for collecting data on unconscious processes. Nevertheless, subliminal paradigms may be valuable for probing arousal mechanisms in the brain that are independent of cognitive modulation , which may have influenced brain function. Furthermore, the ALE approach we adopted does not take into account the relative strength of activation reported by each study, but the present version is essentially a 'vote-counting' method of reported coordinates weighted for the number of participants per study. There were not enough studies examining separately neural activation in males and females, which, as one of the studies has shown  and insular cortex, to form a basis for conscious perception. Activation of primary visual areas by non-consciously perceived stimuli is perhaps driven by a bias for these studies to use images of emotional faces, and so more fMRI studies are needed to compare subliminal and supraliminal presentation of other types of stimuli in different modalities. After further fMRI studies comparing the neural correlates of subliminal versus supraliminal stimulation, meaningful conclusions are more likely to be drawn about brain systems involved in unconscious perception.


BDNF Val66Met polymorphism on transcranial direct current stimulation (tDCS)-induced plasticity in older adults. Here we respond to several key issues raised in regard to our findings, and discuss broader implications for the field of non-invasive brain stimulation (NBS).In a commentary on our recent paper . However, a broader search of the extant literature suggests that the effects of the BDNF Val66Met polymorphism on tDCS-induced plasticity are varied, even before one considers the interaction of tDCS effects with neural activation resulting from performing a concurrent motor task . On the other hand, some studies do not report statistically significant differences between Met carriers and Val/Val homozygotes  are needed to further elucidate a number of factors that may contribute to the divergent results across the existing literature.In addition, there appears to be some preliminary evidence to suggest that the specific polarity of tDCS may interact with BDNF to elicit different magnitude changes in plasticity. That is, putative LTD-like effects induced by cathodal tDCS appear to be somewhat less affected by the BDNF Val66Met polymorphism effects on NBS-induced plasticity in older populations, it is worth reviewing extant research that has investigated the effects of this polymorphism on cognitive and motor function in young and aged populations.Another important consideration is the role that altered brain states and processes may play in mediating plastic responses. Indeed, it has been suggested that in stroke patients, rather than being detrimental, the Met allele interferes with maladaptive brain plasticity such that Val/Val and Met carrier stroke patients may not differ in their absolute ability for recovery . Finally, in addition to probing the genetic effects on artificially induced-plasticity using NBS and use-dependent plasticity using motor/cognitive training paradigms, understanding how the interaction between these two forms of plasticity is mediated by genotype would provide a novel basis to extend research on the effects of this polymorphism.RP and MRH prepared, wrote, and revised the manuscript.This research was supported under the Australian Research Council's Discovery Projects funding scheme (DP130104317) and by a DECRA fellowship (DE120100729) awarded to MRH.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.


Background Return-to-work (RTW) within a complex organizational system can be associated with suboptimal outcomes. Purpose To apply a sociotechnical systems perspective to investigate complexity in RTW; to utilize system dynamics modeling (SDM) to examine how feedback relationships between individual, psychosocial, and organizational factors make up the work disability system and influence RTW. Methods SDMs were developed within two companies. Thirty stakeholders including senior managers, and frontline supervisors and workers participated in model building sessions. Participants were asked questions that elicited information about the structure of the work disability system and were translated into feedback loops. To parameterize the model, participants were asked to estimate the shape and magnitude of the relationship between key model components. Data from published literature were also accessed to supplement participant estimates. Data were entered into a model created in the software program Vensim. Simulations were conducted to examine how financial incentives and light duty work disability-related policies, utilized by the participating companies, influenced RTW likelihood and preparedness. Results The SDMs were multidimensional, including individual attitudinal characteristics, health factors, and organizational components. Among the causal pathways uncovered, psychosocial components including workplace social support, supervisor and co-worker pressure, and supervisor-frontline worker communication impacted RTW likelihood and preparedness. Interestingly, SDM simulations showed that work disability-related policies in both companies resulted in a diminishing or opposing impact on RTW preparedness and likelihood. Conclusion SDM provides a novel systems view of RTW. Policy and psychosocial component relationships within the system have important implications for RTW, and may contribute to unanticipated outcomes. Returning to work after an occupational injury or illness can be a complex process. In an ideal scenario, injured workers follow a uniform return-to-work (RTW) trajectory that consists of a series of evolving phases including seeking medical care, recovery and sustained work re-entry . In manyWithin the context of contemporary biopsychosocial models of work disability –6, studiScientists in the field of work disability prevention are increasingly discussing the need to take a systems-focused view towards examining complexity , 6, 12. Building on qualitative findings, researchers may draw on sociotechnical systems theory which considers organizations as complex adaptive systems made up of interdependent personal, social, technical and organizational components that interact with one another in frequently non-linear ways, and thus can make processes like RTW less uniform , 20. By This study describes a novel application of a sociotechnical systems perspective to better understand the RTW process. In particular, SDM was used to identify and model complex non-linear relationships among key components of organizational work disability systems, and generate quantitative simulations to understand how varying work disability-related policies might impact the likelihood of successful RTW.A multi-staged model building methodology was applied to develop the organizational SDM and will be summarized in the following sections . An in-dModels were developed within two companies in the United States that reported having complex RTW problems. The first was a food manufacturing company, and second was an industrial service company. Despite their differences, the types of job demands performed by frontline workers , and organizational structures were similar.Stakeholders representing various positions across each company’s organizational hierarchy were invited to participate. To be eligible, participants had to be fluent in English, over the age of 18 years, and have direct or indirect experience with the RTW process. Each company provided a list of eligible participants to the investigators. Potential participants were contacted via email or phone and invited to participate. Individuals who agreed to participate in model building received lunch for their involvement. A total of 30 stakeholders took part in model building, 15 from each company. Participants included senior managers , frontline supervisors (n = 10), and frontline workers (n = 10).Participants engaged in two to three iterative model building sessions that were conducted in one-on-one (senior managers) or focus group-style formats (frontline workers or frontline supervisors). Each session lasted between 60 and 90 min, and occurred over the participant’s lunch break. Overall, participant time commitment ranged from 2 to 3 h. During model building sessions, diverse perspectives regarding the RTW process within each organization and integrated insights were collected and incorporated into a representative SDM . To miniModel builders facilitated discussions that elicited the structure and process of the work disability system in each company, while concurrently translating conversations into visual mapping of the SDM . QuestioComponents uncovered through interviews and focus groups were clustered into common themes and translated into dynamic feedback loops by the research team. All feedback loops were described to study participants who were asked for their level of agreement regarding their accuracy in representing the actual process. In cases where there was disagreement, follow-up questions were posed to encourage participants to think critically about the structure of the model. Based on the responses to the additional questions, the model was iteratively refined until stakeholder agreement on the description of each feedback loop was reached .After determining the feedback structure of the SDM, participants were presented with axes that included a system component on the horizontal axis, and an outcome of the feedback loop  on the vertical axis. Participants were asked to estimate the direction, shape, and magnitude of the relationships between the variables on each axis, forming a reference mode . As partAll qualitative and quantitative data collected from model building was entered into the software program Vensim . In addiThe SDM presented in Fig. First, findings from model building sessions showed that the likelihood of RTW within each organization was influenced by two primary stock (level of outcome) and flow variables (rate of change of outcome). Indicated by their positive polarity, greater levels of functional health status (+) and preparedness to RTW (+), increased RTW likelihood. Stakeholders also identified causal pathways between the level of RTW preparedness, and several factors. Indicated by the negative polarity, increases in supervisor pressure to RTW (−) and role demands outside of work (−) resulted in lower preparedness. Quality of supervisor-frontline worker communication (+), and co-worker social support (+) were components that had an opposing impact, and increased RTW preparedness.The model building exercise also revealed that quality of communication was increased by greater supervisor positivity (+), frequency of RTW conversations (+), and amount of information shared regarding work injury (+). Additionally, the length of absence was linked to several model components including role demands outside of work (+), coworker adjustment to workplace injury (+), and supervisor pressure on an injured worker to RTW (+).Despite similarities in terms of components and feedback relationships uncovered through model building, each company implemented unique policies . At the same time, light duty was also related to increased pressure frontline co-workers placed on injured workers to RTW at full duty (+).Next, using the SDM designed in the participating organizations, simulation scenarios were conducted to determine how their unique work disability-related policies influenced the RTW process. The model simulated system behavior over a time period of 24 weeks to capture both simple and prolonged work disability cases. Simulations were examined with respect to their impact on percentage of RTW preparedness  and percentage of RTW likelihood  which were used as proxies for the overall performance of the RTW process [In Company A, where a bonus was provided as an incentive to prevent work injuries, simulations were conducted to compare the current (base case) company-wide bonus  to increased , decreased , and no bonus ($0) scenarios. The simulation presented in Fig. In Company B, where light duty was provided to facilitate early work reintegration, the availability of full light duty (base case) was compared to partial and no light duty. The simulations showed that RTW likelihood Fig. c and RTWThe SDM developed in this study provided a unique view of the RTW process and demonstrated that organizational work disability systems may be viewed as complex, consisting of individual, psychosocial, and organizational components connected by dynamic feedback relationships. Additionally, this study identified potentially critical causal pathways within the system that may explain and quantify how employer-based work disability policies influence RTW trajectories. Characteristic of complex adaptive systems, quantified model simulations found that the implementation of work disability-related policies can result in unanticipated consequences for RTW outcomes. By examining RTW as a system we may inform the ways in which policies and programs are applied within complex organizational systems. More research is required to determine the fidelity of SDM as a research and practice tool in the field of work disability prevention.SDM offered a lens to capture qualitative and quantitative systematic characteristics of RTW in two organizations. Consistent with previous biopsychosocial models of work disability , 5, the Model building also revealed that the two participating organizations differed in terms of the policies they accessed to manage work disability. Policies implemented included an incentive-based preventative policy (Company A) and early light duty provision (Company B). Despite differences in their mechanisms and intended impact, both policies directly effected psychosocial components including supervisor and co-worker pressure on injured workers to RTW. As shown in model simulations, the influence of policies on psychosocial components could potentially result in the emergence of RTW outcomes that were not initially anticipated by employers. Simulations conducted in Company A compared a base case bonus scenario to scenarios with lower and higher bonuses. Findings showed that offering financial incentives decreased RTW preparedness and RTW likelihood. Based on the SDM structure, offering a financial bonus amplified co-worker and supervisor pressure and dampened RTW outcomes, helping to explain the results. This finding is consistent with previous studies examining the use of financial incentives to improve occupational health outcomes , 30. TheSimulations conducted in Company B, examined the impact of light duty availability on RTW. In scenarios where light duty was available, RTW preparedness and likelihood increased. At the same time, the expected difference between the impact of providing light duty versus no light duty on RTW was not as large as anticipated. Using the SDM as a guide, light duty provision might have amplified co-worker pressure and constrained RTW. These findings could suggest that providing light duty to an injured worker may also negatively impact organizational processes , which may have resulted in the pressure placed on injured workers. Consistent with previous research , 17, 18,As a methodology, SDM has potential implications for managers by providing a tool for system-based decision-making. Through a greater awareness of the multiple feedback relationships that make up the system, decision-makers may be able to better understand more complex work disability problems and consider new creative solutions so that the behavior of the system fits with organizational goals . In-deptGiven its novelty in the field of work disability, the limitations of SDM methodology should be acknowledged. First and foremost encouraging stakeholders to engage in systems thinking and it’s respective methodologies can be challenging, especially for those who view RTW as a step-by-step process . To promComplexity is an inherent feature of the RTW process that can underlie variable and often undesirable outcomes. This study was one of the first to apply a sociotechnical systems perspective and SDM methodology to examine complexity in the RTW process, specifically with regard to two industrial companies. Results from model building in both companies showed that individual, social and organizational components and their feedback relationships made up the work disability system and influenced RTW. Psychosocial workplace components could be important leverage points within the system that have the greatest effect on RTW outcomes. The policy-psychosocial component pathway had important implications for the RTW process and may result in RTW outcomes that are not initially anticipated. In sum, a sociotechnical systems perspective provides a unique tool to advance the field of work disability prevention, and inform the ways in which policies and programs are designed and implemented within complex systems.


Rapid maxillary expansion (RME) is an effective orthopedic procedure that can be used to address problems concerned with the growth of the midface. This procedure also may produce positive side effects on the general health of the patient. The aim of the present consensus paper was to identify and evaluate studies on the changes in airway dimensions and muscular function produced by RME in growing patients. A total of 331 references were retrieved from a database search (PubMed). The widening of the nasal cavity base after midpalatal suture opening in growing patients allows the reduction in nasal airway resistance with an improvement of the respiratory pattern. The effects of RME on the upper airway, however, have been described as limited and local, and these effects become diminished farther down the airway, possibly as a result of soft-tissue adaptation. Moreover, limited information is available about the long-term stability of the airway changes produced by RME. Several studies have shown that maxillary constriction may play a role in the etiology of more severe breathing disorders such as obstructive sleep apnea (OSA) in growing subjects. Early orthodontic treatment with RME is able to reduce the symptoms of OSA and improve polysomnographic variables. Finally, early orthopedic treatment with RME also is beneficial to avoid the development of facial skeletal asymmetry resulting from functional crossbites that otherwise may lead to functional and structural disorders of the stomatognathic system later in life. Dentofacial orthopedic treatment, in particular rapid maxillary expansion (RME), is indicated for a wide variety of clinical conditions routinely faced by the orthodontist . FrequenMaxillary constriction can be associated with several problems that include occlusal disharmony and esthetics as well as such functional difficulties as narrowing of the pharyngeal airway, increased nasal resistance, and alterations in tongue posture, resulting in retroglossal airway narrowing and mouth breathing –5.RME is an effective orthopedic procedure that has been used routinely in growing patients for over half a century. The goal of RME is to open the midpalatal suture, providing appropriate and stable maxillary width increase , 7. BecaAlthough this therapy is carried out to correct dental and skeletal maxillary transverse discrepancies, some investigators have shown that treatment outcomes also could involve increasing nasopharyngeal airway dimensions, leading to improved nasal breathing –10. ConsTraditionally, studies on the changes in upper airway dimensions have consisted of analyzing the RME posttreatment effects with two-dimensional (2D) cephalometric radiographs. Recently, the reduction in radiation dose obtained with cone beam computed tomography (CBCT) and low-dose multislice computed tomography (CT) has allowed the development of software capable of computing nasal airway volume .Airway changes induced by RME treatment have been studied by means of functional examinations such as rhinomanometry  and acoustic rhinometry . These diagnostic procedures indicate a significant decrease in nasal airway resistance with consequent improvement in nasal breathing –15.Polysomnography (PSG), commonly referred to as a “sleep study,” is considered the gold standard for diagnosing conditions such as obstructive sleep apnea. This diagnostic regimen provides various quantitative parameters to evaluate respiratory function such as oxygen saturation and Apnea–Hypopnea Index (AHI) .Other diagnostic tools also have been introduced in orthodontics, such as electromyography (EMG), which is used to analyze the activity of the masticatory and facial muscles. EMG, a simple method of detecting and registering electric activity of muscle fibers, has been shown to have good reproducibility , 18.The aim of our consensus paper was to identify and qualify the evidence of reports evaluating changes in airway dimensions and muscular function in patients treated with RME during the growth period. Studies using radiography, CBCT, magnetic resonance imaging (MRI), PSG, EMG, and ultrasound (US) were considered for this purpose. The focused questions were the following: What are the effects of RME therapy on airways, nasal cavity, and breathing function? Are these changes stable in the long term? Do children undergoing RME therapy to correct a transverse discrepancy have any long-term benefit in muscular activity?In order to identify relevant studies about the impact of RME on a child’s general health, a computerized database search was conducted using the Medline database (Medline/PubMed). The search covered the period up to March 2015. The terms used in the search were “rapid palatal or maxillary expansion” in combination with “general health,” “oral health,” “breathing,” “OSAS,” “facial musculature,” “muscle activity,” and “chewing”  of the upper airway. Tecco et al.  observedThe examination of the upper airway plays an important role in the evaluation of the growth and general health of subjects with breathing disorders. Because of the great complexity of airway anatomy and function, several measurement methods have been proposed. These methods can complement each other in the assessment of changes in breathing function after RME , 34.De Felippe et al. , by meanEnoki et al.  evaluateIwasaki et al.  used CBCFastuca et al. , 38 evalThe Apnea–Hypopnea Index (AHI) can be used to indicate the severity of sleep apnea. Evaluating AHI as a secondary outcome, Fastuca et al.  found anSeveral studies have shown that maxillary constriction may play a role in the etiology of more severe breathing disorders such as obstructive sleep apnea (OSA) in growing subjects , 11. OSAOSAS results in oxygen desaturation and arousal from sleep, thus bringing several signs and symptoms related to oxygen desaturation and sleep fragmentation . ImpaireUnder physiological conditions, the nose accounts for 50 % of respiratory resistance. Nasal obstruction related to both anatomical–structural and functional causes is an important risk factor for OSAS. Reducing nasal resistance, therefore, is one of the main objectives of therapy with RME. By widening the palate, RME increases the volume of the nasal and buccal cavities, thus helping to reduce nasal resistance , 42.Several investigators have analyzed growing patients from 6 to 13 years of age with oral breathing, snoring, and nighttime apnea history treated with RME. These studies have demonstrated that at the end of orthopedic treatment, RME was effective in children affected by OSAS without any other obvious obstruction of the upper respiratory airways. RME therapy widened the nasal fossae and released the septum, thus restoring normal nasal airflow with the disappearance of obstructive sleep disordered breathing –45.Marino et al.  evaluateThe use of RME to enhance respiratory function was more effective in OSAS children with bimaxillary retrusion. Maxillary retrusion has been suggested to constrict the upper airway including the nasal cavity and velopharynx and affect airway size or ventilation .Over a 36-month follow-up period, Villa et al.  observedPirelli et al.  evaluateGuilleminault et al.  conducteIt is well accepted that occlusal factors may influence and cause functional disturbances of the masticatory system . In partSeveral investigators have demonstrated through tomographic evaluation asymmetric condylar position in centric occlusion in children with unilateral posterior crossbite, due to an anterior and inferior position of the condyle within the glenoid fossa on the non-crossbite side compared with that of the crossbite side –54. DuriThe functional mandibular shift also is related with postural adjustments. EMG studies have shown that the activity of the temporal and masseter muscles in functional crossbite patients is disturbed . The posDe Rossi et al.  found thThe asymmetrical mandibular position induces different development of the elevator muscles on each side of the jaws leading to a thinner masseter muscle on the crossbite side, which already can be seen in the early mixed dentition . EgermakThus, crossbite is a morphological malocclusion that seems to predispose to functional disturbances, which might be taken as indicating treatment as early as possible . RME is RME is an effective orthopedic procedure used to treat structural and functional problems in the midface. Such treatment has been shown to have positive side effects on the general health of the patient. The widening of the nasal cavity base, found after midpalatal suture opening in growing patients, allows for the reduction in nasal airway resistance and improvement in the respiratory pattern. The significant improvement of the volume of the upper airway that remains stable in the long term suggests a fundamental role of dentofacial orthopedics in the treatment of not only maxillary constriction but also of constrictions of the nasopharyngeal spaces associated with oral breathing, snoring, and obstructive sleep apnea syndrome during childhood. The effects of RME on the upper airway, however, have been described as limited and local, and they diminished farther down the airway, possibly as a result of soft-tissue adaptation. Moreover, very limited information is available about the long-term stability of the airway changes produced by RME. Several studies have shown that RME can be beneficial in the treatment of maxillary constriction associated with more severe breathing disorders such as obstructive sleep apnea (OSA) in growing subjects.Early orthopedic treatment with RME also is beneficial in avoiding the development of facial skeletal asymmetry that may lead to both functional and structural imbalances in growing patients. If left uncorrected, such a functional shift may lead to the development of temporomandibular disorders and other related conditions later in life.


This mini-review focuses on noninvasive brain stimulation techniques as an augmentation method for the treatment of persistent auditory verbal hallucinations (AVH) in patients with schizophrenia. Paradigmatically, we place emphasis on transcranial magnetic stimulation (TMS). We specifically discuss rationales of stimulation and consider methodological questions together with issues of phenotypic diversity in individuals with drug-refractory and persistent AVH. Eventually, we provide a brief outlook for future investigations and treatment directions. Taken together, current evidence suggests TMS as a promising method in the treatment of AVH. Low-frequency stimulation of the superior temporal cortex (STC) may reduce symptom severity and frequency. Yet clinical effects are of relatively short duration and effect sizes appear to decrease over time along with publication of larger trials. Apart from considering other innovative stimulation techniques, such as transcranial Direct Current Stimulation (tDCS), and optimizing stimulation protocols, treatment of AVH using noninvasive brain stimulation will essentially rely on accurate identification of potential responders and non-responders for these treatment modalities. In this regard, future studies will need to consider distinct phenotypic presentations of AVH in patients with schizophrenia, together with the putative functional neurocircuitry underlying these phenotypes. Auditory verbal hallucinations (AVH) are defined as auditive perceptions involving a verbal aspect in the absence of a provoking external stimulus  is elctroconvulsive therapy (ECT). For patients with schizophrenia a meta-analysis of 10 double-blind RCT showed a significant effect for ECT  and specific symptoms of schizophrenia (AVH and negative symptoms)  is of special interest given converging multimodal imaging evidence suggesting a crucial role in AVH generation and perception  and “symptom interference”  MRI studies have been conducted to investigate neural activation patterns in schizophrenia patients experiencing treatment-resistant AVH (Lawrie et al., It is noteworthy that although the lateral prefrontal and temporal cortices clearly are involved in AVH generation, there is also good evidence suggesting a role of cortical midline regions in AVH symptom expression. Abnormal cerebral blood flow could also be detected not only in the primary temporal cortex and Broca’s area, but also in the cingulate cortex (Wolf et al., When treating AVH in patients with schizophrenia using focal stimulation techniques, the clinical endpoint appears to be clearly defined. In the vast majority of cases, this is at least a reduction in overall AVH severity. Yet it should be kept in mind that schizophrenia is a phenomenologically heterogeneous disorder with several distinct phenotypic presentations at both the clinical and neurobiological level, and the very same heterogeneity also applies to persons with chronic AVH. In addition, the multidimensionality of AVH has been long acknowledged by phenomenological research (Kronmüller et al., per se, a major focus of future research will be the identification of markers which can predict stimulation treatment response. An approach which might prove to be helpful for predicting responders and non-responders in the future is subtyping AVH patients according to both neurobiological and clinical criteria. For instance, it has been attempted, albeit with limited success, to improve responsiveness to rTMS by targeting the site of maximal neural activation associated with the hallucinatory event (Slotema et al., Apart from refining and technically developing stimulation techniques McCarthy-Jones and colleagues proposed different subtypes of AVH, which might respond to different treatment modalities. These subtypes may be identified at the levels phenomenology, cognition, neurology, etiology, treatment response, diagnosis, and voice hearer’s own interpretation (McCarthy-Jones et al., In the past decade non-invasive brain stimulation techniques became increasingly relevant for the treatment of drug-refractory AVH. Evidence for ECT for specifically treating AVH is very limited. There is evidence for beneficial effects of rTMS over left temporal and temporoparietal areas, but effect sizes for this treatment modality are moderate, and beneficial long-term effects are unlikely. It has been suggested that rTMS may reduce aberrant internally generated activity associated with AVH at the site of stimulation. Still, the role of rTMS in changing aberrant network function putatively involved in the generation of AVH has to be clarified. A further major challenge for future research is identifying of patients who do respond to treatment and those who do not or only insufficient. Supported by neuroimaging evidence, the magnitude of left STC activity has been promoted as a potential predictor of clinical improvement. Given the phenomenological diversity of schizophrenia and AVH in particular, it is expected that subtyping patients with AVH will essentially contribute to identify responders from non-responders for focal augmentative therapies. In this respect, in accordance with other authors we strongly advocate further development of reliable and valid psychometric assessments and neurobiological markers paralleling the optimization of future stimulation protocols. Other neuromodulatory interventions, such as tDCS provide very promising data as well but larger trials are needed.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.


Risk factors for post-surgical adhesions following gynaecological surgery have been identified, but their relative importance has not been precisely determined. No practical tool exists to help gynaecological surgeons evaluate the risk of adhesions in their patients. The purpose of the study was to develop an Adhesion Risk Score to provide a simple tool that will enable gynaecological surgeons to routinely quantify the risk of post-surgical adhesions in individual patients.A group of European gynaecological surgeons searched the literature to identify the risk factors and the surgical operations reported as carrying a risk of post-surgical adhesions. Through consensus process of meetings and communication, a four-point scale was then used by each surgeon to attribute a specific weight to each item and collective agreement reached on identified risk factors and their relative importance to allow construct of a useable risk score.Ten preoperative and 10 intraoperative risk factors were identified and weighed, leading to the creation of two sub-scores to identify women at risk prior to and during surgery. The Preoperative Risk Score can range from 0 to 36, and the Intraoperative Risk Score from 3 to 31. Several thresholds between these limits may be used to identify women with low, medium, and high risk of post-surgical adhesions.Gynaecological surgeons are encouraged to use this Adhesion Risk Score to identify the risk of adhesions in their patients. This will allow better informed use of available resources to target preventive measures in women at high risk of post-surgical adhesions. Postoperative adhesions are a frequent complication of abdominopelvic surgery , 2. AdheDespite advances in surgical techniques, the healthcare burden of adhesion-related complications has not changed in recent years , 7–10. WThe mainstay treatment for adhesions is adhesiolysis. However, reformation of adhesions occurs in most patients (mean 85 %) regardless of the method of adhesiolysis used or the type of adhesion being lysed .Intraoperative use of adhesion–reduction agents is based on the rationale that contact between two areas of injury is necessary to form an adhesion. These agents act as barriers between injured areas, significantly reducing the development of adhesions –20. HoweApart from population-based epidemiological research , 21–23, A consistent method to identify women at high risk of adhesions following gynaecological surgery is currently lacking. This prompted us to progress this expert consensus project to collectively review the literature with our own experience as gynaecological surgeons, to develop a consensus-based Adhesion Risk Score.Members of the consensus expert panel designed and agreed on the process described hereafter.As the first step, systematic reviews, randomised control trials/controlled clinical trials, cohort studies and meta-analyses published in English specifically addressing postoperative adhesions, adhesion prevention, and adhesion–reduction agents were searched via Medline using key words—post-surgical adhesions, abdominal adhesions, peritoneal adhesions and gynaecological surgery adhesions. No time limit on publication was employed.During a first meeting, the expert panel collectively identified and agreed the risk factors for post-surgical adhesions reported in the literature, and divided them into preoperative, intraoperative, and postoperative risk factors.A second meeting determined the precise wording of risk factors and, where applicable, the values and thresholds of numerical variables. The meeting decisions were then circulated within the panel and each member was asked to rate each risk factor using a scale from 1 (low risk of adhesions) to 4 (very high risk of adhesions).During the third and last round of the consensus process, discrepancies regarding the relative weight of each factor were resolved through face-to-face meetings or phone/e-mail discussions. Following field testing of the scoring in routine practice in ~ 40 patients at 4 centres, thresholds for low, medium, and high risk of post-surgical adhesions were determined at a final meeting to ratify the project.From review of the emerging literature, it was clear that among the published epidemiological and clinical studies, many dealt with adhesions following abdominal surgery in general or non-gynaecological interventions such as colorectal surgery; others were dedicated to complications of adhesions such as small bowel obstructions. Such studies were not considered relevant for our purpose. Those specifically addressing adhesions following gynaecological surgery were comparatively few.During the first meeting, we agreed that the most valuable sources of information on risk factors were several consensus position papers , 24–27, The SCAR-2 study was a retrospective assessment of adhesion-related readmissions in 24,046 patients undergoing gynaecological laparotomic or laparoscopic surgery. This study demonstrated that the risk of adhesion formation, and subsequent complications, varied depending on the anatomical site of the intervention, at least if the laparotomic method had been chosen.We collectively agreed the risk factors for post-surgical adhesions reported in the literature, taking into account known risks due to patient history, surgical technique, side effects of the operation and the anatomical sites of gynaecological surgery—and sub-divided them into preoperative, intraoperative, and postoperative risk factors.Analysis of the selected publications revealed general consensus on several other risk factors, including the total number of abdominal and pelvic surgeries a patient underwent, bleeding, tissue trauma, and the use of foreign materials. However, there was no indication in the literature of the risk level inherent to these risk factors.We reviewed the literature data with our own clinical experiences, following the successive steps of the process described in the “A second meeting determined the precise wording of risk factors and, given the paucity of published evidence, we assigned risk values and thresholds of numerical variables. We agreed on a list of risk factors which were considered simple to assess in routine clinical practice and whose relative importance we rated from one to four.Seven preoperative, ten intraoperative, and three postoperative risk factors were retained. After discussion, we decided that for clinical utility, the Adhesion Risk Score should be simply divided into two sub-scores, namely the Preoperative Adhesion Risk Score; incorporating the identified Postoperative Risk Factors and ‘risk factors associated with previous operations’; and the Perioperative Adhesion Risk Score. These constitute the total Adhesion Risk Score (ARS) shown in Table Two widely accepted classifications published in the literature were used to facilitate the rating of two risk factors. For the Preoperative Adhesion Risk Score, we used the Revised American Society for Reproductive Medicine classification of endometriosis to determine whether the severity of endometriosis, if present, falls into the minimal (rated one), mild (rated two), moderate (rated three) or severe category (rated four) . For theMeeting decisions were circulated within the panel and each member rated each risk factor using a scale from one (low risk of adhesions) to four (very high risk of adhesions).Tables The Adhesion Risk Score presented here was developed from comprehensive searching of the literature and review of pertinent publications, and expert consensus process. It is the first practical tool proposed for gynaecological surgeons to use in their routine surgical practice to evaluate the risk of post-surgical adhesions in individual patients.The two sub-scores (Preoperative and Perioperative) have a similar objective—to help surgeons identify women at particular risk of post-surgical adhesions in a consistent fashion, and from this to make better informed decisions on targeting use of adhesion–reduction agents where resources limit their ability to use them widely.The Preoperative Adhesion Risk Score may be calculated to evaluate the individual adhesion risk level specific to each woman prior to any gynaecological operation. This should thus help the surgeon to adapt the surgical technique as necessary, and decide whether the woman should receive an adhesion–reduction agent, and which one—considering the type of pathology and surgical procedure to be undertaken. No less importantly, it also reminds the surgeon of the necessity to ensure that patients are informed of the potential risks of adhesions before their surgery, thus not only fulfilling their duty of care, but also avoiding potential for medicolegal litigation , 26. TheAs well as potentially identifying further increased risk, the Perioperative Adhesion Risk Score may also help identify those women who may appear to have a low Preoperative Adhesion Risk Score, but who are nevertheless at considerable risk of adhesion formation because of specific risk factors directly linked to the operation process and/or to the characteristics of pre-existing adhesions not known on preoperative assessment. In those women who are then identified as at high risk, the use of an anti-adhesion agent would not only be of likely clinical benefit but also more easily economically justifiable where resources are limited.Although calculating the Perioperative Adhesion Risk Score during surgery may seem impractical, this can be simply addressed by having the Perioperative Adhesion Risk Score available as a poster or on screen in the operating room as an aide memoire. The score can then simply be calculated without impacting on the duration of the surgical process—only 10 numbers ranging from zero to four need adding together.Prior to the development of this Adhesion Risk Score, we were aware of the heterogeneity of data on risk factors for adhesions reported in the literature. Indeed, wide variations exist in adhesion classification and surgical approaches, making comparison between the published evidence difficult. This hampered a fully objective determination of the risk level associated with each adhesion risk factor and the development of a properly evidence-based risk score. Alongside a comprehensive review of the literature, the expert panel consensus process provided the most appropriate method to develop the Adhesion Risk Score presented here.Due to both the heterogeneity and paucity of data on the relative importance of risk factors for adhesions following gynaecological surgery, by consensus, we adopted a simplified scoring process with the weight attributed to each risk factor counted from one to four instead of the one to nine range generally adopted .Within this context, proposing an accurately graded evidence-based evaluation of the risk of post-surgical adhesions in individual women would have been far too ambitious. However, we believe that the three broad categories of low, medium, and high risk proposed should help surgeons better identify women who may benefit most from preventive measures to minimise post-surgical adhesions, providing improved justification and targeting of use of adhesion–reduction agents in healthcare systems where resources and funding are limited.Cost considerations must be taken into account when deciding whether an adhesion–reduction agent should be used. Healthcare providers do not generally refund the cost of adhesion–reduction agents. Gynaecological surgeons participating in two surveys of adhesions awareness conducted in Germany  and in sAs operating surgeons, we have to better target all our existing resources and while fully recognising the seriousness and extent of the problem of adhesions, a key issue we sadly face is justifying the use of an adhesion–reduction agent. We encourage gynaecological surgeons to use the Adhesion Risk Score to evaluate the risk of adhesions in their patients in a consistent fashion and thus assist in making both better informed decisions and justification for use of appropriate preventive measures in high-risk patients, especially in younger women identified as at high risk of adhesions who wish to conceive.We acknowledge that our Adhesion Risk Score is a first attempt that may need refinement after testing in broader routine surgical practice. While building an evidence-based risk score using an appropriate statistical method  is clear


There is a growing realization that the gut–brain axis plays a key role in maintaining brain health and the stress response. Recently, the gut microbiota has emerged as a master regulator of this axis. Thus, opportunities to exploit the microbiome to treat stress-related psychiatric disorders are materializing. Clinical validation of such strategies is now warranted. The paradigm giving rise to such therapies dates back to the 1950s, and efforts by the pharmaceutical industry to develop therapies based on alternative paradigms have proved relatively fruitless. Over the past decade another paradigm has begun to emerge, whereby there is a growing realization that the gut–brain axis, the bidirectional communication between the digestive tract and the brain, plays a key role in maintaining brain health and the stress response. More recently, the gut microbiota has emerged as a master regulator of this axis. Indeed, preclinical studies have shown that the microbiome is key to normal neurodevelopment and behavior , raisingIt has been postulated that the brain–gut–microbiota axis plays a fundamental role in stress-related mental illnesses . The totHow fundamental are gut microbes for brain function? Studies from a number of research groups in Canada, Sweden and Ireland have shown that, in germ-free animals, the brain fails to develop normally in the absence of the gut microbiome. Moreover, fundamental brain processes such as myelination, adult neurogenesis and microglia activation have also shown to be critically dependent on microbiota composition. Bercik and colleagues  showed tMajor depression is a highly prevalent, debilitating stress-related disorder and is recognized globally as one of the significant causes of disability, with considerable social consequences. The most consistently demonstrated abnormality in depressed patients is hypothalamic–pituitary–adrenal (HPA) axis dysregulation, manifested as elevated cortisol and corticotropin releasing factor (CRF). Furthermore, significant increases in the plasma concentrations of pro-inflammatory cytokines are usually observed.Bifidobacterium infantis. Published studies in rodents indicate that treatment with this probiotic does impact on central neurotransmitter functioning.Microbes exert a major influence on both the HPA axis and on the immune system, compounding the link between the microbiota and the stress response. Sudo and colleagues  were theLactobacillus rhamnosus strain (JB-1) on anxiety- and antidepressant-related behavior, in addition to neurochemical changes in mice. L. rhamnosus-treated animals had lower levels of anxiety on a variety of behavioral measures, which was concomitant with alterations in the expression of both GABAA and GABAB receptors across a variety of brain regions studied. Yet the question remained as to how a dietary intake of a bacterial strain could alter brain and behavior. One possible route of communication is via the vagus nerve. To test this, animals underwent vagotomy or sham surgery and were subsequently treated with L. rhamnosus or an inactive control broth. Indeed, vagotomy prevented the behavioral and neurochemical effects of the potential probiotic strain, suggesting that L. rhamnosus could serve as a potential antidepressant/anxiolytic via its (or one of its metabolites) effects on the vagus nerve. Studies are currently underway to examine the effect of this microbe on stress responses in humans; preliminary results should be available shortly.A number of years ago, together with Bienenstock and colleagues at MacMaster University , we examIn what is the largest study of the microbiome in major depressive disorders to date, Jiang and colleagues  analyzedBifidobacterium longum strain 1714 attenuated stress responses and enhanced cognition in healthy subjects while altering electroencephalographic activity. Mayer’s group at the University of California, Los Angeles (UCLA) found that a cocktail of bacteria produced significant changes in central physiology, as measured by altered activity in functional magnetic resonance imaging (MRI) [Live bacteria that have a positive mental health benefit have been defined as psychobiotics . Severalng (MRI) .Until very recently, the literature on psychobiotics was dominated by preclinical studies with little or no effort at translation into humans. Fortunately, this situation is now changing, with several human studies being undertaken (see ). HowevePsychobiotics enable an increase in the level of “good” bacteria within the intestine and offer a potentially safe approach to treating stress-related conditions. Alternatively, the elimination of certain microbes using selective antimicrobial agents may have a positive mental health benefit in some individuals. Preclinical studies and initial patient-based studies indicate the potential of the antibiotic minocycline as an antidepressant . MinocycOnly time will tell if the brain–gut–microbiota axis proves a fruitful target for novel antidepressant development. It seems likely that psychobiotics have a role to play in the management of mild depression and anxiety states. Although animal studies have been, and continue to be, essential in deciphering the mechanisms underlying potential psychobiotic effects, we now await future translation into human clinical investigations and the results of large-scale placebo-controlled trials.


Yet, in a recent paper, Desender et al.  in which salient task-irrelevant features either help  or hinder  task-relevant processing. An important exercise within this domain is to obtain a clear understanding of the concept of conflict, and of the precise circumstances under which it arises and triggers behavioral adaptations. Throughout the last century various proposals have circulated  congruency. This indeed confirms that other sources than item (in) congruency drove conflict levels in the brain.By explicitly differentiating item (in)congruency and conflict, conflict monitoring theory opened up the possibility that—in principle—the two can be functionally dissociated, as sources other than item (in)congruency (see below) can contribute to conflict (and thus to adaptation) as well. Yet, although widely assumed across computational cognitive control models  can only work at the level of consious conflict experience. Instead, we would argue that expectancies , may equally well have a direct impact at the level of conflict generation  sources can drive conflict generation in the brain. Interestingly, various computational models (Botvinick et al., 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.


Current theories suggest that the brain is the sole source of mental illness. However, affective disorders, and major depressive disorder (MDD) in particular, may be better conceptualized as brain-body disorders that involve peripheral systems as well. This perspective emphasizes the embodied, multifaceted physiology of well-being, and suggests that afferent signals from the body may contribute to cognitive and emotional states. In this review, we focus on evidence from preclinical and clinical studies suggesting that afferent thermosensory signals contribute to well-being and depression. Although thermoregulatory systems have traditionally been conceptualized as serving primarily homeostatic functions, increasing evidence suggests neural pathways responsible for regulating body temperature may be linked more closely with emotional states than previously recognized, an affective warmth hypothesis. Human studies indicate that increasing physical warmth activates brain circuits associated with cognitive and affective functions, promotes interpersonal warmth and prosocial behavior, and has antidepressant effects. Consistent with these effects, preclinical studies in rodents demonstrate that physical warmth activates brain serotonergic neurons implicated in antidepressant-like effects. Together, these studies suggest that (1) thermosensory pathways interact with brain systems that control affective function, (2) these pathways are dysregulated in affective disorders, and (3) activating warm thermosensory pathways promotes a sense of well-being and has therapeutic potential in the treatment of affective disorders. The proposition that mental illnesses are brain disorders has become a foundational principle guiding funding priorities at the National Institutes of Health. On the face of it, this seems an altogether reasonable course of action. After all, given the high likelihood that mental states arise from functional states of the brain, what other kind of disorders could mental illnesses be?The answer to this apparently rhetorical question is that mental disorders in general—and major depressive disorder (MDD) in particular—may be embodied conditions that derive causality in non-trivial ways not just from the brain, but also from domains that lie outside the central nervous system (CNS). Indeed, significant research now suggests that human emotions, cognition and behavior arise not just from the activity of brain circuitry, but also from our sensory-motor experience in relation to multiple aspects of the environments in which we find ourselves. At its most radical, the concept of embodiment suggests—to quote a recent review—that “the brain is not the sole cognitive resource we have available to us to solve problems. Our bodies and their perceptually guided motions through the world do much of the work required to achieve our goals, replacing the need for complex internal mental representations”  and their treatment, both the classic five senses  and senses such as the sense of ambient light by intrinsically photosensitive retinal ganglion cells (ipRGCs), kinesthetic sense, pain, temperature, and immune signaling that function to report on the internal state of the body. However, in this paper we focus specifically on thermosensory pathways and their CNS targets, based on increasing evidence that they hold significant promise, both in deepening our understanding of the biology of MDD and in enhancing our capacity to treat it. We commence by describing the integrated circuitry by which peripheral thermal information is conveyed to, and processed by, the CNS. We then review evidence linking thermosensory phenomena and biology  with affective states in general and with depression in particular. Following this we provide evidence that thermosensory pathways function abnormally in MDD. We conclude with recent evidence—based on studies using whole-body hyperthermia (WBH)—that peripheral thermosensory pathways may hold promise as novel treatment modalities for MDD.This section focuses on pathways by which thermal information is transferred from the periphery to the CNS, and how—within the CNS—different aspects of thermosensory information are processed. We focus on non-noxious thermal stimuli because, as we discuss at several junctures, these appear to be most relevant to both the pathophysiology and treatment of mood, and perhaps anxiety, disorders. In this section we first trace afferent thermosensory pathways to the CNS, then discuss brain regions involved in the various aspects of thermal perception and conclude by reviewing evidence that these brain regions function abnormally in individuals with mood disorders and may be restored to more appropriate activity levels following antidepressant treatment.In this section we explore mechanisms through which cutaneous warmth signals to the CNS. It is important to recognize the difference and often complete dissociation between skin temperature and core body temperature and their functional relation. Skin temperature and core body temperature are functionally interrelated and vary in a diurnal pattern. Sleep typically occurs during a circadian phase of increased heat loss, which is due to both a decrease in heat production as well as an increase in skin blood flow and the associated skin warming and transfer of heat to the environment  dorsal horn Craig, . SomatosGiven the distinction between nociceptive and non-nociceptive thermal sensory signaling, even at the level of lamina I of the spinal dorsal horn, we focus in this review on thermal signals within the non-noxious range. There are many reasons to restrict the focus. For example, the molecular mechanisms of non-noxious warm signaling  are different from noxious heat   that project to the preoptic area to mediate sympathetic and shivering thermogenic responses and also metabolic and cardiac responses  that also project to the preoptic area and play a role in heat defense (thermoregulatory cooling)  in the brainstem  objects and local ambient temperatures. This research examines the overlap between the processing of physical temperature information and any corresponding change in psychological states associated with temperature, such as metaphorical warmth or coldness , poor support , and childhood neglect/abuse  provide the best model for predicting depression in a 12-month period , it is important to note that not all studies have found these relationships. For example, Donnellan et al.  have recWhile the effects of physical warmth on interpersonal warmth have received considerable attention, the effects of interpersonal warmth on physical warmth  have received less attention. There is some evidence to support the hypothesis that interpersonal warmth increases cutaneous warmth, due to an increase in cutaneous blood flow, which is associated with thermoregulatory cooling. For example, one study found that brief social contact by the experimenter to intimate parts of the body (the face or chest) of an experimental subject, but not social contact to the outer arm or palm, induced increases in facial and chest temperature of the individual being touched, and these effects tended to be greater when the social contact was from an opposite-sex experimenter relative to a same-sex experimenter  and noxious  range  and noxious  ranges , was first made in 1890 , a number of studies have documented reduced skin conductance responses to auditory stimuli  in depressed patients, particularly patients with psychotic depression. Moreover, studies have found that electrodermal hyporeactivity is particularly associated with a history of suicide attempts  axis reactivity, low sympathetic reactivity, high parasympathetic reactivity, and low testosterone  disorder. Interestingly, as with melancholia, both conditions have been associated with increased core body temperature. Women with late luteal phase disorder demonstrate increased core body temperature when compared to women without the condition  increase linearly with the number of DSM-IV accessory atypical depressive symptoms  share in common mechanisms of action that simultaneously impact multiple areas of brain functioning, only a portion of which are likely to confer antidepressant benefit  specificity in our interventions. This insight fuels current enthusiasm for both deep brain stimulation and transcranial magnetic stimulation . Findings discussed below regarding the anatomical specificity of peripheral thermosensory pathway—CNS interconnectivity point to a different, but complementary, approach. Rather than attempting to alter neurocircuit functionality by technological methodologies , it may be possible to harness anatomic/functional specificity built into peripheral sensory signaling pathways by evolutionary processes to selectively impact functioning in specific brain regions linked in animal and human studies to depression and well-being.Supporting this approach, prior studies suggest that altering functional activity in such peripheral sensory pathways—in this case the innate immune inflammatory response—produces antidepressant effects without incurring some of the disadvantages inherent in directly manipulating the CNS with either drugs or devices. For example, utilizing a randomized, placebo-controlled design in 60 patients with treatment-resistant depression, we found that peripheral blockade of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha with a biologic agent too large to cross the blood-brain-barrier (infliximab) produces antidepressant effects similar in magnitude to those seen with standard antidepressants in individuals with elevated baseline concentrations of peripheral inflammatory biomarkers , while having no effect, or a detrimental effect compared to placebo, in patients with progressively lower baseline levels of these same biomarkers   with reduced signaling in the just-described afferent thermoregulatory pathway that mediates heat defense by inducing thermoregulatory cooling to maintain thermal homeostasis, it is clear that sub-optimal activity of this pathway would likely be associated with increased core body temperature as a result of impaired thermoregulatory cooling. Said more simply, elevated body temperature in depression reflects sub-optimal thermoregulatory cooling capacity. Indeed, because evidence suggests that the spinoparabrachial pathway that runs to thermoregulatory areas of the dorsal raphe nucleus also activates higher brain areas associated with positive emotional states, decreased activity in this pathway should produce both impaired thermoregulatory cooling (hence increased body temperature) and depressed mood. Conversely, stimulating this pathway should reduce body temperature and improve mood. Because WBH appears to activate this pathway, one would predict that it should have antidepressant effects and lower body temperature. We turn now to evidence that this is the case.Mycobacterium vaccae) also activated DRI serotonergic neurons and resulted in increased serotonergic activity in cortical areas repeatedly implicated in the pathogenesis of MDD ] that are implicated in both thermoregulatory cooling and antidepressant and anti-anxiety behavioral effects  and then back to the periphery (via descending thermoregulatory cooling pathways) one might predict that depressed subjects with evidence of abnormalities in this skin-to-brain-to-skin (S2B2S) circuit might be more likely than other depressed individuals to respond clinically to WBH. Although multiple readouts of S2B2S are likely to exist based on its functional anatomy , the most direct measure of its activity is likely body temperature. People with sub-optimal S2B2S functioning would be expected to have impairments in thermoregulatory cooling and therefore to show elevations in core body temperature. Thus, following this line of reasoning, increased body temperature at baseline, potentially indicating dysregulation of thermoregulatory function, should—somewhat paradoxically—be associated with enhanced antidepressant responses to hyperthermia.SD = 10.6) pre-treatment to 19.2 (SD = 12.3) 5 days post-treatment   = 5.15 p < 0.001, effect size = 1.4]. Interestingly, the antidepressant response observed 5 days post-treatment was actually improved 6 weeks later in nine patients for whom these longer-term follow-up data were available (CES-D mean score 13.9). Although these patients received additional treatment during this period, these findings, while preliminary, suggest that WBH may induce a rapid antidepressant response that can be solidified by longer-term modalities. We were able to obtain 24-h mean core body temperature at baseline and post-treatment day 5 for 7 of our patients who received WBH. A single session of WBH significantly reduced mean circadian core body temperature 5 days post-treatment , suggesting that WBH enhanced thermoregulatory cooling capability. Moreover, consistent with the possibility that the S2B2S circuit represents a functionally unified pathway, reductions in core body temperature from pre-treatment to post-treatment day 5 showed a large effect size correlation with reductions in depressive symptoms over the same period   = 0.62, p = 0.043]  for discriminative processing. Consistent with the dichotomy between discriminative and affective processing of warm temperature, distinct pathways mediate the discriminative and affective responses to pleasant touch. CLTMs project to inner lamina II of the spinal dorsal horn Sugiura, , which rRecent studies show that ketamine, a rapid acting antidepressant drug currently in development for treatment of affective disorders, activates the same positive affective circuits that we have highlighted here for WBH. That is, the medial orbitofrontal cortex, ventral striatum, and the dorsal anterior cingulate cortex, extending into the pregenual cingulate/callosal region , evidence converges on the perspective that thermosensory and thermoregulatory processes meaningfully contribute to the affective experiences of humans and non-humans alike. The extant literature points to bidirectional relationships between experiences with physical temperatures and affect, in both clinical and non-clinical populations. How important these thermosensory and thermoregulatory relationships will turn out to be in comparison to other biological and social factors that contribute to well-being and mental disorders remains an open question, the answer to which will ultimately determine the clinical utility of much of what has been discussed in this article. Based on preliminary findings from our group that a single session of WBH induced a rapid, large and sustained reduction in depressive symptoms in adults with major depression  increase one's propensity to sweat. A novel hypothesis derived from the ideas in this article is that increased sweating in response to these antidepressants should be associated with a degree of clinical improvement, because sweating is a potential read-out for activity in afferent thermosensory/regulatory pathways.A final—and perhaps most radical—prediction is that people who respond best to a peripheral intervention like WBH might be found to have less architectural pathology within the CNS than those who don't respond and who might require a more CNS-specific type of intervention. Said differently, those most likely to benefit from stimulation of peripheral afferent thermosensory/regulatory pathways may have depression with a causal locus more completely located outside the CNS than those who don't respond. Nonetheless, these possibilities need to be balanced against the high likelihood that in many cases interactions between stimuli, sensory process, and changes in CNS function will turn out to be as relevant to pathogenesis as abnormalities isolated to any particular element in the skin-to-brain-to-skin thermosensory/regulatory circuit described in this article. As appears to be the case more generally, depressive pathology may well be distributed across the functioning of thermosensory/regulatory systems and may result to a significant degree from poor functioning of the system in its entirety.However future research weighs in on these hypotheses and predictions, at the least it seems safe to say at this point that, given the importance and ubiquity of thermal sensations for all of human experience, further inquiry into the relationship between thermosensation, serotonergic neural activity, thermoregulation, and emotional well-being is warranted.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.