Robotic-assisted surgical techniques are not yet well established among surgeon practice groups beyond a few surgical subspecialties. To help identify the facilitators and barriers to their adoption, this belief-elicitation study contextualized and supplemented constructs of the unified theory of acceptance and use of technology (UTAUT) in robotic-assisted surgery. Semi-structured individual interviews were conducted with 21 surgeons comprising two groups: users and nonusers. The main facilitators to adoption were Perceived Usefulness and Facilitating Conditions among both users and nonusers, followed by Attitude Toward Using Technology among users and Extrinsic Motivation among nonusers. The three main barriers to adoption for both users and nonusers were Perceived Ease of Use and Complexity, Perceived Usefulness, and Perceived Behavioral Control. This study's findings can assist surgeons, hospital and medical school administrators, and other policy makers on the proper adoption of robotic-assisted surgery and can guide future research on the development of theories and framing of hypotheses. Technological innovations have spawned the development of new surgical techniques. For certain operations, open surgery has given way to standard laparoscopic and robotic-assisted surgery, in which surgeons use micro equipment through small incisions This study attempts to elicit common beliefs among surgeons to contextualize the unified theory of acceptance and use of technology (UTAUT) in robotic-assisted surgery. The elicited beliefs, obtained from in-depth interviews, are used to identify dominant UTAUT constructs. Consequently, this study attempts to answer two research questions: 1) What are the most important facilitators and 2) barriers to surgeon's adoption of robotic-assisted surgery?So far, little research has been conducted on this topic and, as with other health technologies, the application of theory to the study of physicians' behavior has been limited The following paragraphs briefly review the advantages and disadvantages of open, laparoscopic, and robot-assisted surgery :Open surgery consists of cutting skin and tissues to expose organs and other structures. Open surgery provides direct access to the operative site with depth perception and dexterity for one or more sets of hands. Open surgery is the only option for many procedures and for certain kinds of patients . However, open surgery usually requires a long incision, which leaves a visible scar. The trauma caused in gaining access to the organs can result in a more painful recovery, a longer healing process, prolonged hospital stays, a higher risk of infection Minimally invasive procedures have advantages for certain kind of operations A surgical robot is a self-powered, computer-controlled manipulator that can be programmed to aid in positioning and manipulating surgical instruments This study focuses on the da Vinci surgical system because of its extensive use in diverse subspecialties The use of robotic systems has been gaining popularity in several surgical subspecialties, such as cardiac, thoracic, urological, gynecological, pediatric, and general surgery Physicians' adoption of a technology is highly self-governed because of the specialized services they provide Lack of acceptance may be attributed to the challenges of coping with new devices, adapting new kinds of instrumentation, and learning new operative maneuvers Some surgeons believe traditional practices are sufficient to treat their patients. For example, previous research has found that in general surgery the application of robotic technology has not translated into improved patient outcomes Research on robotic-assisted surgery tends to focus on the development and implementation of the robotic technology and the evaluation of clinical outcomes To provide a better understanding of the facilitators and barriers to surgeons' adoption of robotic-assisted surgery, this research uses the UTAUT model . The UTATo mediate the impact of the four main constructs on usage intention and behavior, four factors are posited: gender, age, experience, and voluntariness of use. The UTAUT model was developed through a review and consolidation of the constructs of eight models that earlier research had employed to explain information technology usage behavior. Validation of the UTAUT model in a longitudinal study found it accounted for about 70% of the variance in behavioral intention  and about 50% of the variation is actual use of the technology Because the UTAUT model has not yet been applied to the adoption of surgical robots, it requires contextualization. Previous research has proposed belief elicitation as the preferred method for contextualizing theories of behavior in a specific setting , with a new population , and a new behavior of interest  The results of the content analysis were organized using the modified UTAUT model . The queThe most discussed main constructs were Performance Expectancy  and Facilitating Conditions . These two constructs had the highest percentage of pro-adoption and contra-adoption comments among users and nonusers . The mosThe comments were separated into facilitators and barriers to adoption. Among the subconstructs, the major facilitators for adoption were Perceived Usefulness  and Facilitating Conditions . The next main facilitators were Attitude Toward Using Technology among users  and Extrinsic Motivation among nonusers . The main barriers to adoption were Perceived Ease of Use and Complexity , Perceived Usefulness , and Perceived Behavioral Control .This study was conducted to find the most important facilitators and barriers to surgeons' adoption of robotic-assisted surgery. To this end, the discussion of the results is divided into six subsections: facilitators, barriers, a comparison of users and nonusers, sample comments, limitations, and contextualized solutions to address the adoption issues.In relation to the proposed modified UTAUT model, Perceived Usefulness, Facilitating Conditions, and Attitude toward Using Technology were the key facilitators of users' adoption of robotic-assisted surgery .Within the Performance Expectancy main construct, the most influential subconstruct (with 221 pro-adoption comments) was Perceived Usefulness. Users were attracted to the many enhanced functions of the robot: better visualization, increased precision, better dexterity, elimination of hand tremor, better suturing, better instrumentation, better angle of placement, easier access, and better ergonomics. Another persuasive element in this construct is that robotic technology improves on standard laparoscopy, allowing the performance of closed surgeries as if they were open. In addition, the users trusted this technology because of the reliability of the robot. In the Extrinsic Motivation subconstruct, improved patient outcomes influenced the surgeons' decision to adopt surgical robots. These positive outcomes include reductions in bleeding, pain, blood clots, infection rate, complication rate, and post-operative adhesions. Personal Outcome Expectations indicated that robotic-assisted surgeons had experienced an increase in patient referrals, which in turn increased job satisfaction.Within the Social Influence main construct, the most influential subconstruct with 40 pro-adoption comments was Subjective Norm. Surgeons viewed robotic technology as market driven. Because of public advertisement, media coverage, and online information, patients are encouraged to seek out the latest technology. These patients are thus attracted to hospitals and surgeons where robotic-assisted surgery is available and marketed. In this study, the users claimed not to care about the effects of performing robotic-assisted surgery on their personal image; users stated that they performed robotic-assisted surgery, because they wanted to improve patient outcomes.Within the Facilitating Conditions main construct, the most influential subconstruct (with 208 pro-adoption comments) was Facilitating Conditions. Surgeons expressed confidence in using this technology because of the support provided by Intuitive Surgical, Inc. A technical support representative is onsite most of the time or easily reached by phone.Attitude Toward Using Technology is another main construct that had a definite impact on the sample's adoption of robotic technology. The construct contains 125 pro-adoption comments made by the robot users. Most users indicated that they have fun performing robotic-assisted surgery. They held high expectations for the future development of this technology, such as the ability to perform surgery remotely and the improved portability of the robot. Development of additional practice-specific instruments will allow the adoption of this technology by other specialties, such as general surgery, cardiac surgery, and plastic surgery. Surgeons also indicated that as they became more experienced using the technology, their technique and comfort level improved. Overall, these surgeons are early adopters The Leadership subconstruct was added to contextualize the UTAUT model for this study. Most robot users are involved in training and proctoring other surgeons and otherwise helping them to adopt this technology. Some of these surgeons also help the manufacturers make instruments more effective and durable. These improvements allow the specialties to accommodate more procedures.In relation to the modified UTAUT model, similar to the users, the results among the nonusers showed that Perceived Usefulness and Facilitating Conditions are the subconstructs that increase surgeons' expected success in adopting robotic-assisted surgery .Within the Performance Expectancy main construct, the most influential subconstruct with 99 pro-adoption comments was Perceived Usefulness. Persuasive elements in this construct were similar to those identified by robot users. The Social Influence main construct has a slightly positive influence on robotic-assisted surgery adoption with 10 pro-adoption comments. Robot nonusers expressed sentiments similar to those of users: that the technology is market-driven. Within the Facilitating Conditions main construct, the Facilitating Conditions subconstruct has 67 pro-adoption comments. Even robot nonusers aware of the good onsite technical support. Training provided by the technical support team was also identified as a positive influence on surgeons' likelihood of adopting robotic technology in the future.In relation to the modified UTAUT model, the results among the users showed that Perceived Usefulness, Perceived Ease of Use and Complexity, and Perceived Behavioral Control were the major barriers to the adoption of robotic-assisted surgery .Within the Effort Expectancy main construct, Perceived Ease of Use and Complexity, the only subconstruct, received 86 contra-adoption comments. Among the contra-adoption comments, a steep learning curve was a major barrier. Surgeons were accustomed to feeling the organs, including the amount of pressure being applied to an organ, during an operation. However, that tactile feedback is lost with robotic technology. Surgeons stated they needed to perform at least 25 operations to learn to ‘feel’ with their eyes. Another element that slowed the decision to adopt robotic technology is the setup of the robot, which is cumbersome and time-consuming.The results among the nonusers showed that Perceived Usefulness, Personal Outcome Expectation, Perceived Ease of Use and Complexity, and Perceived Behavioral Control were the four major barriers to the adoption of robotic-assisted surgery .Like the users, within the Effort Expectancy main construct, Perceived Ease of Use and Complexity was the best represented subconstruct with 62 contra-adoption comments. Among the contra-adoption comments, a steep learning curve was again a major barrier. A lack of tactile feedback is the main reason. Unlike robot users, nonusers did not want to take the time to learn to ‘feel’ with their eyes, and they did not want to learn on their patients. Another barrier was increased operative time because of the time required to set up the robot.Performance Expectancy is another main construct that has a negative impact on the adoption of robotic technology among nonusers. Among its subconstructs, Personal Outcome Expectation contained 33 contra-adoption comments, and Extrinsic Motivation contained 24 contra-adoption comments. Some nonusers stated that robotic-assisted surgery is merely a marketing tool. In OB/GYN and urology, some robot nonusers said they were losing patients to surgeons who perform robotic-assisted surgery. In cardiothoracic surgery, some surgeons could not justify using a robot because of limited patient volume for the procedures in which a robot can be used.Despite the advantage of improved post-operative patient outcomes , some noWithin the Facilitating Conditions main construct, Perceived Behavioral Control had 42 contra-adoption comments. Nonusers noted that hospitals had not encouraged them to perform surgery with the robot. The perceived return on investment was low: Although the robot is an expensive piece of equipment, reimbursement from private insurance companies and Medicare is the same as for regular laparoscopic procedures. Therefore, because the potential for economic gain seemed marginal, surgeons did not want to invest time in learning to use the robot.Users expressed concerns about the same problems anticipated by nonusers, thus confirming the validity of nonusers' concerns. For example, Perceived Usefulness has been often cited both as a facilitator and a barrier to adoption among both users and nonusers. Both Perceived Ease of Use and Complexity and Perceived Behavioral Control were mostly cited as a barrier, whereas Facilitating Conditions was mostly cited as a facilitator in both groups. Thus, addressing the concerns of users and nonusers may help both groups.Surgeons' comments provide additional insights into the facilitators and barriers to the adoption of robotic-assisted surgery. For example, the following comment reveals concerns that should be addressed by hospital administrators, medical schools, and policy makers:What scares me to death is that right now the urologic trainees in the US are going to be the most poorly trained urologists surgically that have ever come out of our training program… because surgeries have become minimally invasive, either laparoscopically or robotically. So if the surgeon gets into trouble, nobody in the whole ward knows how to slice the patient open and stop the bleeding to control the problem.To represent some of these concerns, a selection of common comments is included in Because the focus of this research is on the sample's acceptance or rejection of robotic-assisted surgery, the results are limited to one group of stakeholders and do not include the views of patients, hospitals, and robotic equipment makers. The research questions concern the surgeons' point of view, and the research framework was designed around a few factors with a direct constraint on the scope of this study. These factors include the impact of performing robotic-assisted surgery versus traditional procedures, surgeons' culture, the overall success or failure of robotic-assisted surgery, the familiarity and usage of robotic technology in surgery generally, and the differences in perceptions and opinions between surgeons. This study is limited to interviewing surgeons from Indiana; it is not a representation of all the surgeons in the US or surgeons in other countries that use robotic-assisted surgical techniques. Another limitation of this study is the sample size.One potential bias in this research study is that all robotic-assisted surgeons who were interviewed were using the da Vinci surgical system. Their experiences do not necessarily represent the experiences of surgeons using other robotic systems or surgeons working outside the US. Another potential bias is one of self-selection: surgeons who agreed to be interviewed may have been particularly interested in this technology. In contrast, the surgeons who declined to be interviewed may have had valid input, but were not sufficiently interested to participate.The modified UTAUT model requires revalidation in a quantitative follow-up study owing to the addition of the Attitude Toward Using Technology and Leadership constructs. It is important to determine whether these constructs have validity, including incremental validity, in the context of robotic-assisted surgery.This qualitative research has adapted the UTAUT model and contextualized it for robotic-assisted surgery. Extending the research entails further quantitative approaches to measure the detailed impact of each construct in the adoption process; however, based on the results of this study, the major UTAUT constructs affecting both users and nonusers are highlighted and thus various solutions can be contextualized to promote the facilitators and remove the barriers. For example, Perceived Usefulness has been expressed as both a main facilitator and barrier to the adoption of robotic-assisted surgery among both users and nonusers. The detailed comments reveal that the surgeons fall in one of three categories regarding evidence supporting adoption: they are seeking the best medical evidence supporting the usefulness of robotic-assisted surgery; they are unaware of published supporting evidence; or they do distrust the evidence. Validating available outcome-based evidence, disseminating it among potential users, and conducting new clinical trials may alleviate or confirm concerns about robotic-assisted surgery.Robotic technology will play an increasingly important role in surgery The results show that most surgeons were attracted to the benefits provided to their patients by performing surgery robotically. Another important factor was the surgeons' attitude: Robot users were more open to change and enjoy the adventure of learning new technologies. Even though they acknowledged the steep learning curve for robotic-assisted surgery, they recognized the potential advantages. Several barriers recognized by the nonusers are the steep learning curve, the lack of incentives or encouragement from the hospitals, and the high cost of the robot. For surgeons to adopt robotic technology, these issues must be addressed. To overcome the lack of tactile feedback, hospitals should provide more opportunities for surgeons to practice using robotic techniques. Robot manufacturers should also investigate haptic technologies for providing tactile feedback.In Indiana only 14% of hospitals have surgical robots, though they are more prevalent in the greater Indianapolis area. Their high cost is still a barrier for rural hospitals. In Indianapolis, surgeons have more opportunities to gain experience with surgical robots by scrubbing in with a practiced surgeon. Once they can perform robotic-assisted surgery on their own, their patient population is likely to increase in practices lacking robotic surgeons.Contextualization of the UTAUT model resulted in the merger of some of the subconstructs and the addition of two new main constructs: Attitude toward Using Technology and Leadership. The new modified UTAUT model will enable future research to further enhance the application of technology acceptance models to robotic-assisted surgery. Further quantitative measures, such as scaled questionnaires, can be created based on the modified UTAUT model to measure the prediction rate of each UTAUT construct in the adoption of robotic-assisted surgery. This has practical implications, because it will enable researchers, healthcare managers, and policy makers to measure the readiness of their surgeons in adopting robotic technology.We believe that conducting this elicitation study with surgeons will lead to more refined, contextualized theories of robotic-assisted surgery acceptance and use. This development is similar to previous studies in other industries To understand surgeons' perspectives on robotic-assisted surgical technology, this study's data was collected through semi-structured interviews. This qualitative method was selected, because little prior research has been conducted on surgeons' adoption of robotic surgical systems and, therefore, the most relevant issues have not yet been identified. Semi-structured interviews gather detailed information about each surgeon's beliefs and behaviors without preconceived factors; the method provides opportunities for identifying unanticipated outcomes and is effective in understanding attitudinal and behavioral nuances in the situated context This study was approved on May 28, 2008 by the IUPUI/Clarian Research Compliance Administration. The study approval ID is EX0805-47. Informed consent was obtained in writing from all participants immediately before the interviews commenced. The content of the consent form was approved by the above Institutional Review Board. The signed consent form of each participant will be retained for three years. All stored data is deidentified.The sample population was comprised of surgeons in Indiana who practice in robotic-assisted surgery subspecialties. A sample of surgeons was recruited by telephone from a list provided by the Indiana State Medical Association. The goal was to recruit approximately 20 surgeons with a roughly equal number of users and nonusers in each subspecialty. Sixty-eight surgeons were contacted. Among the surgeons agreeing to interviews, 21 were selected and interviewed between June 18 and August 21, 2008 at their offices. Ten of the surgeons were using the da Vinci robot, and the remaining 11 were not. The participating surgeons were from the following specialties: urological surgery, cardiovascular surgery, cardiothoracic surgery, obstetric and gynecological (OB/GYN) surgery, and general surgery.SD = 1.9 years). The largest age group among users was 40–49 years (50%). Surprisingly, the largest age group among nonusers was younger: 30–39 years (45%). Eighteen of the 21 participants (86%) were male: Nine of 10 users (90%) and 9 of 11 nonusers (82%).In this study's sample, 4 of 7 OB/GYN and 4 of 7 urology surgeons were robot users. By contrast, only 1 of 4 surgeons in the cardiovascular specialty and 1 of 3 in general surgery were robot users. Among the robot users, there was considerable variation in the number of robotic surgeries performed annually. For example, one surgeon used robotic technology in 100% of surgical cases, averaging 200 to 250 cases per year, whereas another surgeon used robotic technology in less than 2% of surgical cases (just 4 of 150 to 200 cases per year). On average the users had performed robotic-assisted surgery for 3.7 years  participant data triangulation—facts and opinions provided by one participant were checked by other participants to build a coherent justification for the choice of constructs; and (2) member-checking—each participant evaluated the accuracy of his or her categorized comments. Five participants proposed minor corrections to their comments, which were then incorporated into the results.Appendix S1Interview Guiding Framework(DOC)Click here for additional data file.Appendix S2Demographics Questionnaire(DOC)Click here for additional data file.


Depression is one of the major contributors to the Total Disease Burden and afflicts about one-sixth of Western populations. One of the most effective treatments for depression focuses upon analysis of causal chains in overt behaviour, but does not include brain-related phenomena as steps along these causal pathways. Recent research findings regarding the neurobiological concomitants of depressive behaviour suggest a sequence of structural and functional alterations to the brain which may also produce a beneficial outcome for the depressed individual--that of adaptive withdrawal from uncontrollable aversive stressors. Linking these brain-based explanations to models of observable contingencies for depressive behaviour can provide a comprehensive explanation of how depressive behaviour occurs and why it persists in many patients. Principally via its harmful effects on health, relationships and cognitive performance -4, deprepurpose or outcome of behaviour for the organism exhibiting it . Whe. Whe53]]amygdala , and cel the PFC  and hipp the PFC . There a the PFC  and betw the PFC . These o the PFC ,33. ThosThe accepted symptomatologies of depression  highlight the specific presence of apathy and anhedonia, which are localised to the reward circuits in the limbic system that are heavily reliant on dopamine , leadingThese structural changes to the amygdala, PFC and hippocampus also induce elevated anxiety behaviour, which may then instigate even greater elevation of hypothalamic responses to stress. When the individual is threatened, the activation of the amygdala stimulates the hypothalamus for fight-or-flight responses. By contrast, the hippocampus has an inhibitory effect upon the hypothalamus , principThese findings suggest a model of depression in which a circuit including the PFC, amygdala and hippocampus influences not only mood regulation, but also learning and contextual memory processes . SpecifiThese details are important in forming a causal chain that links environmental stressors to depressive behaviour because, when connectivity is disrupted between the integrative and executive functions of the lateral orbital PFC, rostral PFC, medial PFC, dorsolateral PFC and dorsal ACC on one hand, and the emotional/visceral functions of the ventral ACC and ventral medial PFC, plus the hippocampus, amygdala and nucleus accumbens on the other hand, the brain undergoes a decrease in regulatory feedback from the former "rational" regions to the latter "emotional" regions . This alAs indicated above, the amygdala enlarges and the PFC and hippocampus shrink either before or during the initial stages of depression, producing a more emotion-oriented response pattern in the depressed individual, principally via elevated activation of the HPA axis, hypercortisolaemia, increased hypothalamic activity and downstream increases in SNS activity. Although this emotionality might initially appear to be at odds with the relatively "flat" affect that is symptomatic of depression, it may more easily fit within the early stage of depression, when the patient is faced with uncontrollable aversive environmental events. When faced with that kind of insurmountable environmental stressor, the relative usefulness of completely rational problem-solving strategies is probably low, simply because of the powerlessness experienced by the depressed individual when they consider their situation rationally. That is, compared to emotional responses that may enhance the individual's likelihood of (even by chance) finding a strategy out of the uncontrollable aversive situation they are in, rational thinking may be less likely to be selected by environmental pressures. In addition, these heightened emotional responses in the face of uncontrollable aversive stressors may result in the depressed individual becoming extremely frightened and even behaviourally "freezing" or withdrawing, and thereby avoiding further unwanted aversive outcomes. This phenomenon of "freezing" is common among mammals as a response to a predator and has a functional value in that it shows submission and hence may cause the predator to cease attacking ,97. Freeimmediate adaptive function of withdrawal in the face of uncontrollable aversive environmental stressors, i.e., it performs a function for the depressed person at the time of the stressor. That function may include reduction in the intensity of the environmental stressor's effect upon them, provision of time for reflection on future responses to the stressor, allowing time for the stressor to pass, and as a passive invitation to others to take some responsibility for the depressed individual's welfare. In more modern times, depression may also serve the individual by providing intense nurturing in the form of psychotherapy [However, although several authors have described depression as "evolutionary" in that it has evolved to perform the functions of (1) withdrawing from uncontrollable aversive stressors and allowing the depressed individual time to analyse the stressful situation they find themselves in, and (2) eliciting assistance from partners and close others ,103, thiotherapy , reductiotherapy , reductiotherapy , and widWhen viewed from this perspective, the neurobiological responses of: (i) elevated HPA axis activation in response to overwhelming stressors, followed by consequent hypercortisolaemia, which causes (ii) structural alterations to the amygdala (enlargement) and PFC and hippocampus (shrinkage) that lead to (iii) amygdala dominance of the hypothalamus, causing (iv) more emotional and SNS-focussed behavioural activity patterns, can be understood as a chain of neuro-behavioural responses to threat that may possess some immediate benefit for the individual exhibiting them. Concomitantly to these adjustments to uncontrollable stress, emotional responses to such adversity engender some typical physiological responses including crying , an actiAs well as explaining the link between aversive environmental stressors, withdrawal (depressive) behaviour and escape, plus access to valued environmental consequences via functional analysis as described above, the range of behavioural therapies share the principal effective components of (i) building rapport between therapist and patient ,112, andIf accentuated, the first of these therapeutic strategies  can provide a powerful one-on-one interpersonal rapport experience for the depressed person, and may reduce hypercortisolaemia . SupportThe second major strategy of behaviour therapies is that of behavioural activation, or encouraging the depressed person to engage in behaviours that will bring more positive social and personal enjoyment . By replHowever, these neurobiological effects of behaviour therapies are valuable but often occur without the awareness of behaviour therapists. Based upon the links described above between environmental stressors, neurobiological sequelae, and overt behaviour, several other suggestions may be made so that behaviour therapists might actively incorporate neurobiological data into behaviourally-focussed therapies for depression. First, as well as standard psychological assessment and background information, induction to therapy for depression might include blood or saliva tests for hypercortisolaemia as an indicator of prolonged HPA activation that may lead to organic changes to the PFC, hippocampus and amygdala. Although more invasive, functional MRI assessments of those sections of the depressed patient's brain might also inform initial assessment and provide a baseline for evaluation after treatment. Second, although considered to be an important and existing aspect of those therapies, the level of rapport and support engendered in behavioural therapies should receive major attention because intense rapport has been shown to decrease cortisol (as described above). Therefore, this aspect of the patient-therapist interaction should be more than the superficial friendliness that is part of common professional demeanour -120. ThiAlthough a wealth of research data support the use of behavioural models of depressive behaviour and behavioural therapies for treatment of depression, particularly those which emphasise a functional analysis component, the neurobiological underpinnings of the onset of depressive behaviour and its adaptive consequences for the person exhibiting it  have not been joined in a comprehensive model. Built upon the notions of sickness behaviour as providing a benefit to the infected organism, the concomitant neurobiological alterations to structure and function of various brain regions  that accompany elevated HPA-axis activation following the onset of uncontrollable and highly aversive environmental stressors, may be seen to link observable behaviour with brain function to provide a more comprehensive model of depression. Further exploration of this model via monitoring of brain function during depressive experiences and therapy may help provide more detail for this model and move it towards greater completeness.Financial competing interests: The author(s) declare that they have no competing financial interests.Non-financial competing interests: The author(s) declare that they have no competing non-financial interests.CS conceived the concept and designed the overall paper. He also wrote the sections on neurobiology of depression and about the ways in which the HPA axis links genes, environmental stress and depressive behaviour. VB wrote the section regarding behavioural therapies and functional analysis in depression, and also how the behavioural-brain model could be used in therapy. Both authors approved the final ms.CS.Both authors read and approved of the complete ms.VB is Associate Professor of Clinical Psychology and Behaviour Management, a State-Registered Clinical Psychologist, and has interests in behavioural and functional analysis of therapies for depression.CS is a Professor of Clinical Neuroscience, with interests in the biological underpinnings of depression and treatment modalities.


The extraordinary progress experienced by sequencing technologies and bioinformatics has made the development of omic studies virtually ubiquitous in all fields of life sciences nowadays. However, scientific attention has been quite unevenly distributed throughout the different branches of the tree of life, leaving molluscs, one of the most diverse animal groups, relatively unexplored and without representation within the narrow collection of well established model organisms. Within this Phylum, bivalve molluscs play a fundamental role in the functioning of the marine ecosystem, constitute very valuable commercial resources in aquaculture, and have been widely used as sentinel organisms in the biomonitoring of marine pollution. Yet, it has only been very recently that this complex group of organisms became a preferential subject for omic studies, posing new challenges for their integrative characterization. The present contribution aims to give a detailed insight into the state of the art of the omic studies and functional information analysis of bivalve molluscs, providing a timely perspective on the available data resources and on the current and prospective applications for the biomonitoring of harmful marine compounds. Next Generation Sequencing (NGS) platforms have been implemented, most notably de novo 454-pyrosequencing of transcriptomes pyrene pyrene . Additioasiliana  whereas asiliana ,22 or caasiliana . Similarstradiol . Interesstradiol  has alsoincialis .Pinctada maxima (BioProject PRJNA114601). Similarly, the expression profile of the digestive gland of the manila clam Ruditapes philippinarum was studied by using an Agilent Oligo Microarray platform (BioProject PRJNA135933) during four seasons in four different areas of the Venice Lagoon. Finally, pharmaceuticals also constitute a new emerging class of environmental contaminants continuously released in aquatic environments. Among them, the effect of exposure to ibuprofen has been already tested on R. philippinarum using microarrays, revealing an alteration of several molecular pathways, including arachidonic acid metabolism, apoptosis, peroxisomal proliferator-activated receptors, and nuclear factor-kappa B, helping elucidate the putative mechanisms of action of ibuprofen in non-model species [Other examples of transcriptomic approaches to the study of anthropic compounds include microarray-based studies of Tributyltin, a chemical biocide used in marine antifouling paints that, in addition to causing shell abnormalities, also affects biomineralization pathways in the oyster Crassostrea hongkongensis, supporting their potential application as diagnostic tools for the assessment of metal pollution in environmental monitoring programs [M. galloprovincialis [Mytilus species [Geukensia demissa [Proteomic approaches are a valuable complement of transcriptomic studies in bivalves and can support the identification of new biomarkers of xenobiotic toxicity . For insprograms . Moreoveincialis . The pro species ,113,114  demissa . OverallThe great relevance of marine invertebrates makes the lack of bivalve model organisms puzzling. Still, the information reviewed throughout this work supports two bivalve molluscs, the Pacific oyster and the blue mussel, as upcoming model organisms. This notion is sustained by progressive omic characterizations of these organisms during the last decade, unleashing many potential applications most notably for pollution biomonitoring. Yet, the implications of bivalve omics for other research fields are still unexplored. Given the high bioaccumulation rates associated with the filtering capacity of bivalves and their relative tolerance to xenobiotics, it would not be surprising if new useful marine compounds, proteins or whole metabolic pathways could be discovered as a result of the omic analysis of these organisms. Although the possibilities promise to be endless, the development of further applications is still hampered by the early stage of development of omic technologies and associated computational methods of data analysis in bivalve molluscs, definitely far behind traditional model organisms. In such a scenario, and given the nature of the omic data, the advance in the integrative knowledge of bivalves will require coordination and transfer of knowledge across researchers sharing complementary goals. Indeed, the release of web accessible databases containing processed and reviewed results (not simply raw data) seems the best way to consolidate the omic characterization of bivalve molluscs. Altogether, great expectations are placed on future bivalve omics as it pertains to life sciences, environmental sciences and aquaculture livestock managing. Nonetheless, there is undoubtedly a long road ahead to obtain a truly holistic understanding of the basic features displayed by the different bivalve omes.


The anterior segment optical coherence tomography provides an objective method to assess the anterior segment of the eye, including the anatomy of the anterior chamber angle. This technology allows both qualitative and quantitative analyses of the angle and has shown potential in detecting and managing angle-closure glaucoma. In addition, it has a role in identifying pathology in some forms of secondary open-angle glaucoma and postsurgical management of glaucoma. Limitations of this technology include its cost and inability to visualize well structures posterior to the iris, such as the ciliary body. This paper focuses on potential benefits and limitations of anterior segment optical coherence tomography when compared with conventional gonioscopy and ultrasound biomicroscopy. Various clinical entities will be described to discuss its potential role in glaucoma practice. Glaucoma is a progressive optic neuropathy characterized by structural changes in the optic nerve head with corresponding changes in the visual field. While the final pathway involving structural and functional loss is similar for various types of glaucoma, a comprehensive evaluation of the drainage angle is critical for accurate diagnosis and appropriate therapeutic intervention. In the United States, the most common type of glaucoma is primary open-angle glaucoma, whereas primary angle-closure glaucoma is the major form in other parts of the world –4. ThereGonioscopy remains the reference standard for assessing anterior chamber angle in the eye. It is inexpensive, rapidly performed at the slit-lamp, permits dynamic visualization of the entire angle quadrant, and allows indentation differentiating between appositional and synechial angle closure. However, this is a subjective technique and is easily affected by patient cooperation, examiner's skill, type of lens used, direction of gaze, inadvertent pressure on the cornea, and environmental illumination . FurtherImaging of the anterior segment of the eye offers an objective method for visualizing the angle and adjacent anatomical structures. In addition to qualitative analyses, some imaging modalities permit quantitative analyses that can be used to monitor change or progression over time. Several imaging devices are described below to understand potential benefits and limitations of anterior segment optical coherence tomography (AS-OCT).UBM uses high-frequency ultrasound (35–100 MHz) to provide high-resolution images of the angle. A typical UBM system  uses a 50-MHz transducer and provides an axial resolution of 25 um, lateral resolution of 50 um, tissue penetration of 5 um, and 256 A scans at a rate of eight frames per second . This eaThe Pentcam  uses a rotating Scheimpflug camera to provide a 3-dimensional image of the anterior segment of the eye , 16. AltThe EyeCam  was originally designed to obtain wide-field photographs of the retina in pediatric cases . HoweverAS-OCT uses the principle of low-coherence interferometry instead of ultrasound to produce high-resolution, cross-sectional images of the anterior segment of the eye , 20. TheCompared with UBM, this technology provides a higher axial resolution (18 um versus 25 um in 50 MHz UBM) and faster sampling rate (2.0 kHz versus 0.8 kHz). Another main clinical advantage over UBM is its ability to provide noncontact scanning in a seated, upright position. However, the image acquisition can be affected at times by the superior eyelid, and oblique angles may allow cross-sectional images. In addition, image distortions may result from off-axis measurements, requiring special software correction to eliminate the influence of scanning angle and refractive index of the cornea . Lack ofThe two AS-OCT devices commercially available are Visante-OCT  and slit-lamp OCT . Compared with the Visante-OCT, the SL-OCT has lower axial and transverse resolution, slower image acquisition, and requires manual rotation of the scanning beam. The properties of Visante-OCT are listed in The anterior chamber angle refers to the junction between the iris root and cornea. In evaluating the angle, an important anatomic landmark is the scleral spur, which is the connecting point between the posterior curvature of the cornea and the curvature of the sclera. Trabecular meshwork and Schwalbe's line are located anterior to the scleral spur. The iris root and the ciliary body are located posterior to the scleral spur. Once the scleral spur is identified, attention is paid to the position of the iris relative to the scleral spur. If the iris is posterior to the scleral spur, the angle is open. If the iris is anterior to the scleral spur, the angle is either narrow or closed. y = ax + b, is calculated to measure acceleration (a) and the y-intercept (b) to describe various types of angle configurations. Acceleration indicates the rate at which the angle widens from the scleral spur, and the y-intercept describes the distance from the scleral spur to the iris. Negative values for coefficients a and b indicate shallow depth at the central and peripheral parts of the angle, respectively [Anterior segment imaging plays an important role not only in identifying the angle structures qualitatively, but also in providing quantitative measurements by using special software to determine the extent of apposition in cases of angle closure. After the scleral spur is located, several parameters can be measured –35. Anteectively . Because AOD measurements are made in the iris plane, they can be influenced by the presence of peripheral anterior synechiae or other irregularities of iris contour and curvature. To overcome these limitations and to account for the whole contour of the iris surface, Ishikawa et al.  devised Because of poor visualization of the angle recess near the scleral spur and inability to measure the ARA properly with AS-OCT, Radhakrishnan et al.  proposedIdentifying the scleral spur is a critical landmark for both UBM and AS-OCT before calculating other angle parameters. Scleral spur location is reported to be successful in approximately 72% of images obtained with AS-OCT . The difAnatomically narrow angles can be diagnosed with AS-OCT both qualitatively and quantitatively Figures  and 3. RAs different parameters are calculated to assess the angle, it is important to keep in mind that various factors, such as room illumination, accommodation, or medications may affect the shapes and locations of anterior segment structures . In addiAngle closure is characterized by apposition of the peripheral iris to the trabecular meshwork, resulting in obstruction of aqueous outflow. A variety of mechanisms involving the iris, ciliary body, lens, or forces posterior to the lens may be involved in the pathogenesis. Of various etiologies, pupillary block is the most common cause of angle closure and results from lens-iris contact, creating a pressure differential between the posterior and anterior chambers. The increased pressure in the posterior chamber leads to iris convexity with closure of the anterior chamber angle. Laser iridotomy is the definitive treatment for this condition. Equalizing the pressure differential in the two compartments reverses the iris bombe configuration and opens the drainage angle. AS-OCT can be used to diagnose this condition and monitor response to laser iridotomy .Although AS-OCT is limited due to blockage of infrared light by iris pigment with incomplete visualization of the ciliary body, it can visualize iris cyst, iris melanoma, or ciliary effusions in some cases. AS-OCT has been described to differentiate cystic and solid lesions of the iris . HoweverAS-OCT can be used to assess the iris contour in pigment dispersion syndrome (PDS). In this condition, pigment liberation is secondary to rubbing between the iris pigment epithelium and lens zonules because of increased iridolenticular contact. The rubbing results from posterior bowing or concavity of the iris, which, in turn, is due to a reverse pressure gradient between the anterior and posterior chambers. In essence, there is a reverse pupillary block caused by blinking in which aqueous humor is pumped into the anterior chamber by movement of the iris but is prevented from flowing backward because of the valve effect of the iris against the lens . Aptel eThe noncontact nature of AS-OCT makes it a valuable tool in identifying angle pathology in posttraumatic eyes . Angle rAS-OCT is a useful tool to evaluate filtering blebs or glaucoma drainage devices in the postoperative period Figures , and 11.P < 0.001). In contrast, CCT measurement with manual Visante-OCT was higher than with ultrasound pachymetry . Nevertheless, both imaging devices had 95% limits of agreement with ultrasound pachymetry as demonstrated in the Bland-Altman plots. It is well established that CCT influences the accuracy of intraocular pressure measurements obtained with the Goldmann applanation tonometer. Therefore, measuring CCT has become the routine component of glaucoma evaluation. Several types of pachymeters are available for measuring CCT, but ultrasound pachymetry is considered the standard because of its established reliability. However, this technique is limited by being a contact technique, and errors can be introduced by using a probe that can lead to misplacement or corneal compression. AS-OCT has built-in analysis software to measure the CCT automatically without contact with the eye . In addiClinically, it is important for clinicians to be aware of the differences in CCT measurements between AS-OCT and ultrasound pachymetry and caution should be exercised in interpreting CCT obtained from different anterior segment imaging systems. While no technology can be a substitute for a thorough clinical examination performed by an experienced ophthalmologist, AS-OCT is a valuable adjunctive tool for anterior segment imaging, especially the angle anatomy in glaucoma suspects and patients. Its noncontact nature, high-resolution images, rapid scanning speed, storage capacity, imaging in the presence of corneal opacities, and the ability to provide both qualitative and quantitative analyses of the angle recess make it an important diagnostic tool for disease documentation, progression, and therapeutic outcomes. Its limitations should be kept in mind, including cost and its inability to image the ocular structures posterior to the iris due to blockage of wavelength by pigment.


Carcinogenic/toxic effects of ochratoxin A (OTA) in various internal organs of Plymouth Rock chicks were determined. The number of OTA-induced neoplasms was similar in chicks given 25 ppm L-β-phenylalanine (PHE) in addition to 5 ppm OTA compared to chicks given only 5 ppm OTA, which showed that PHE cannot be used as a real protector against the carcinogenic or toxic effects of OTA in chicks. OTA was found to provoke strong degenerative changes in liver and kidneys, degenerative changes and depletion of cells in lymphoid organs, oedematous and degenerative changes in the brain, muscular haemorrhages and fatty changes in the bone marrow. The target organs for carcinogenic effect of OTA in chicks were found to be kidneys and liver. Ochratoxin A (OTA) is a mycotoxin widely encountered in animal feeds and human foods. The most obvious effects of OTA-contaminated feed on chicks are reported to be reduced rates of weight gain ,2,3, decet al. [Feed supplements are often studied with regard to their potential to ensure safely utilisation of some mycotoxin-contaminated feeds. Haazele et al.  reportedet al. ,11. Howeet al. ,11, but et al. . TherefoToxicology Letters [This experiment could be considered as an extension of our former short term studies on the toxic effects of OTA on various internal organs, biochemical indices and body weight gain in stock chicks, published in  Letters . The maiAspergillus ochraceus  with continuous infra-red lighting at a temperature suitable for their age. Commercially prepared complete standard feed  suitable for the breed and age of the chicks according to the accepted standards and regulations of the country, which contained the defined concentrations of OTA with or without PHE supplementation, supposed to protect against the toxic effects of OTA, were available ad libitum during the whole experimental period as described in Specific pathogen-free chicks (Plymouth Rock) were purchased at two-weeks of age, housed in wire floor cages  was used in 5:1 molar ratio with regard to OTA as the higher doses (above 10:1 molar ratio) provide only a slight protection against OTA, because of increasing the absorption of OTA from the stomach and intestine. In addition, the higher supplementation of pure phenylalanine in diets contaminated with OTA also tended to create an amino acid imbalance, which reduced b. w. gain and feed conversion efficiencies ,16.The Trakia University Animal Care Ethic Committee approved the study protocol and chicks were housed, maintained and slaughtered in accordance with the Bulgarian Welfare Regulations.t-test were used to estimate significant differences between tumour incidences in experimental and control groups. All chicks were examined for the existence of various neoplastic tissues at the end of the two years experimental period, when the same were slaughtered. Such examination was also made in all chicks, which were dead during the experiment. Non-parametric Mann–Whitney and Student’s Materials for histological examination were taken at slaughter time (at about 24-months age) or after the death of the chicks from kidneys, liver, heart, thymus, bursa Fabricii, spleen, intestine, cerebellum, brain, medulla and bone marrow as well as from various neoplastic tissues. The same were fixed in 10% neutral buffered formalin or processed for freezing microtome. The freezing materials were stained with Sudan III for proving the fat. The fixed tissues were processed for paraffin embedding, sectioned at 6 µm and stained with haematoxylin-eosin. Periodic acid-Schiff (PAS) stain was also used for proving of lipoproteid, glycoproteid or mucoproteid substances in various tissues and cell components, and especially for proving the thickening of basement tubular membranes (with lipoprotein structure). Some materials were stained according to Weigert iron haematoxylin for proving the presence or absence of fibrin in various cyst formations.The most obvious clinical signs as weakness or dullness, goose plumage, transient diarrhoea and growth depression were seen in all chicks from the groups treated with OTA, but the same were less pronounced in chicks supplemented additionally with PHE. Various nervous symptoms such as torticollis, emprosthotonus, lurch, reeling gait (staggering step) and tremor were seen in different degree in all chicks treated with OTA alone, but only in half of the chicks treated with PHE in addition to OTA. Some of these clinical signs as weakness or dullness were seen just after 2–3 weeks of feeding the contaminated diet, whereas other signs as nervous symptoms appeared after 10–15 weeks, but were more pronounced at the end of the first year of the experiment.At the end of the 10th month of the experiment one male chick from group 1 was dead. Several large grey-white neoplastic spots were seen in the diaphragmatic and abdominal surfaces of the liver in the same chick , which wFour chicks died between the 12th and 24th month from the beginning of the experiment, because of development of different kind of malignant tumours diagnosed as lymphosarcoma in kidney (chick from group 1), adenocarcinoma in kidney (chick from group 2), carcinoma in the region of ureters (chick of group 1—Two more benign tumours were found at the slaughter time (24 months from the beginning of experiment). The same were defined microscopically as rhabdomyoma in the breast muscles  in epithelial cells of the proximal convoluted tubules, cystiform dilatation of the lumen of some tubules, tubular atrophy in other tubules, mononuclear proliferation in the mucosa of ureters, and moderate proliferation of connective tissue and mononuclear cells in the renal interstitium, seen mainly in chicks of OTA-treated group and in lesser extent in chicks of group additionally treated with PHE. Different degree of congestion of peritubular capillaries, oedema, activation and proliferation of capillary- or vascular endothelium and vascular adventitial cells of kidneys were also seen in the same both groups. The existence of various kinds of distended tubules with atypical epithelial cells was also a frequent finding in the kidneys of the same chicks.In the case of the initial solid carcinoma in the region of ureters , many seThe adenocarcinoma of kidneys showed cyst-like formations lined with several layers of atypical cells with polymorphism and large hypochromatic or polychromatic nuclei. Several metastases in the lung were also found in the same chick.The lymphosarcoma of kidneys was accompanied by glomerular or tubular atrophy and large necroses among the neoplastic tissue.The cystic adenomas of kidney had small sizes without destructive growth and penetration in the adjacent parenchyma and were constituted of cyst-like formations lined with one layer neoplastic cells without polymorphism or metastases in the adjacent parenchyma.In the liver, cloudy swelling, granular degeneration and rarely fatty changes of the hepatic cells were seen in the chicks of OTA-treated group, but the same changes were less obvious in the chicks supplemented with PHE. Activation of capillary endothelium and Kupffer's cells, hyperaemia, pericapillary oedema, perivascular mononuclear cell infiltration, proliferation of connective tissue and bile ducts were also noticed, mainly in the chicks of OTA-treated group.In the case of adenocarcinoma in the liver, neoplastic tissue showed infiltrative or destructive growth within adjacent parenchyma and was constituted of cyst-like formations lined with several layers of neoplastic cells  having pThe carcinoma of liver and spleen showed lots of similar neoplastic spots in both liver and spleen. Neoplastic carcinoma cells had an increased polymorphism, large quantity of irregular mitoses, lots of polychromatic nuclei and small necroses among neoplastic tissue . CarcinoIn the thymus and bursa of Fabricius, a depletion of lymphoid cells, atrophy, necroses or cyst formations in the lymph tissue were seen in the chicks of both OTA-treated groups. In the chicks of control group, only atrophy of lymph tissue or lymph follicles as well as proliferation of connective tissue around the follicles, corresponding to the involution of the same organs, were seen. A cellular depletion or degenerative changes were also found in the white pulp and germinal centres of the spleen in the chicks of the both OTA-treated groups. Slight to moderate degenerative changes or depletion of lymphoid cells were also seen in the lymph follicles of intestinal mucosa in the chicks of both OTA-treated groups. A mononuclear and heterophilic cell infiltration was often seen in the lamina propria of intestinal mucosa of the same chicks. Small foci of focal necrosis and loss of surface epithelium accompanied by degenerative changes in the glandular epithelium were found only in the intestinal mucosa of chicks treated with OTA alone.In the heart, granular or vacuolar degeneration, lytic changes or irregular staining as a result of the increased eosinophilia of some myofibrils as well as activation of capillary endothelium and perivascular oedema were mainly seen in the chicks treated only with OTA, while the same changes were less pronounced in the chicks additionally supplemented with PHE.In the case of rabdomyoma in the breast muscle, the neoplastic tissue was constituted of myofibrile-like but not striated muscle cells showing a much paler colour compared to the ordinary myofibrils. Destructive growth or metastases in the adjacent areas were not observed.In the lung, only perivascular or peribronchial mononuclear cell infiltration was found in some chicks of both groups treated with OTA. The pericapillary or pericellular oedema and lytic changes in neurons and glia cells were the most obvious pathological changes in the brain of all OTA-treated chicks. Activation and proliferation of capillary- or vascular endothelium and vascular adventitial cells were seen in some vessels of the brain in the chicks of the group treated with OTA alone. Small foci of proliferation of glia cells around some vessels or necrotic neurons were rarely seen in OTA-treated chicks.Similar oedematous and degenerative changes were also found in the cerebellum, mainly in the region of the Purkinje's cells, in the chicks of both OTA-treated groups. Well visible oedematous changes in the white substance of cerebellum were also found in the chicks treated with OTA alone.In the medulla, lysis and pyknosis of tigroid substance of some neurons were seen mainly in the lumbosacral region in the chicks of the group treated with OTA alone.In the bone marrow, cell depletion and fatty changes were only noticed in the chicks of both experimental groups.No pathological changes or neoplasms were seen in the internal organs of the control chicks. Only a natural involution of the bursa of Fabricius and thymus were found in the same chicks.The neoplasms (tumours) and pathological changes observed in experimental chicks are considered to be due to OTA-exposure, because such pathological changes or tumours were not observed in the control chicks and no infections or other diseases were seen in any of the experimental chicks.Histopathological changes seen in both experimental groups of chicks correspond well to the clinical signs observed. The strong degenerative changes seen in the epithelial cells of the kidneys or the liver could be explained by the route of elimination of OTA via the kidneys and the liver, having in mind, enterohepatic recirculation and hepatobiliar way of excretion of OTA . In suchThe observed karyomegaly in hepatic cells adjacent to neoplastic tissue should be considered as an indicator of the partial regenerative activity of parenchyma in the damaged area . On the On the other hand, various kinds of distended tubules with atypical epithelial cells in the kidneys could be considered as pre-neoplastic kidney lesions in the affected kidneys , whereaset al. [et al. [et al. [et al. [Several line of evidences indicated that carcinogenic effect of OTA is correlated to its genotoxic effect reflected by DNA-adducts formation ,27,28. Iet al. , Castegn [et al. ,31, who  [et al. ,32 this via the liver and not only via the kidneys, which may explain the strong degenerative changes found in livers of OTA-treated chicks. A similar finding of OTA-induced tumours, including liver neoplasms, is also characteristic for mice or rats [The circumstance, that some of the tumours were situated in the liver, in contrast to other farm animals, correspond well to the fact that a large amount of OTA in chicks is also excreted  or rats ,26. UnfoThe found carcinoma in the ureters of chick is really interesting findings, which is in good agreement with the high frequency of carcinoma in the renal pelvis, ureters and urinary bladder found in patients suffering from Balkan Endemic Nephropathy ,34, a diIt has been found that OTA decreases natural killer cell activity by the specific inhibition of endogenous interferon levels . As natuetc. [In field conditions OTA is only part of a complex array of mould metabolites, such as penicillic acid, fumonisins, citrinin, etc. ,40, whicetc. ,42,43,44etc. ,46,47,48etc. ,39,40. AThe utilization of various means to reduce OTA-toxicity (as PHE supplementation) supposes a good understanding of the possible mechanisms of OTA-toxicity: an inhibition of enzymes involved in phenylalanine metabolism , an effect on lipid peroxidation, an effect on mitochondrial function (inhibition of ATP production), an ability to provoke a dose-related increase in sister chromatid exchange (SCE) in Chinese hamster ovary cells (CHO) and to cause DNA single-strand break ,26,49,50It was surprising however, that the protective effect of PHE in the present experiment was significantly lower than our expectation. This could be explained by the circumstance that PHE was found to increase the absorption of OTA from the stomach and intestine as well as the gastrointestinal transit of OTA resulting in fourfold up to eightfold higher levels of OTA in serum, as has been reported in some experiments with mice . On the In this study we demonstrated that OTA induces significant pathomorphological damages in kidneys, liver, lymphoid organs, brain and bone marrow of chicks, as well as some tumours in kidneys, ureters, liver, spleen and muscles. A significant protection of PHE against the carcinogenic or toxic effects of OTA in chicks was not observed in the present experiment.


Therapeutic options currently available for neonatal seizures are still unsatisfactory both in terms of efficacy and of risk for long-term neurotoxicity, even if there is growing recognition of their potential to worsen neurodevelopmental outcome. A recent paper by Slaughter and colleagues entitled “Pharmacological treatment of neonatal seizures: a systematic review” has been published with the aim to provide a treatment algorithm, but, due to the relative paucity of clinical studies, it relies mainly on traditional antiepileptic drugs and does not distinguish between different neonatal populations, especially preterm and hypothermic neonates, who might require a dedicated approach in order to improve seizure control and reduce side effects. Neonatal seizures therapy is still a controversial issue in neonatal neurology as drug options are limited and disappointing, whereas failure to control them with antiepileptic therapy has been associated with a worsening in subsequent outcome , urgentlThe effects of neonatal seizures on the immature brain are difficult to distinguish from those of the brain lesions causing them, however the presence of prolonged seizures in the neonatal period represents an important risk factor for poor prognosis or developing neurological sequelae . With anDespite the high potential risk of adverse neurological outcome in newborns with prolonged seizures, there are currently no efficacious therapies.Slaughter et al.  have recIn view of the available evidence a treatment algorithm is proposed, starting with IV phenobarbital as the first-line drug (possibly to be repeated once) followed by either IV levetiracetam, phenytoin/phosphenytoin or lidocaine as second-line and, in case of refractoriness, a trial of pyridoxine followed by IV midazolam. Last options considered include pentobarbital coma or lidocaine (unless previous administration of phenytoin/phosphenytoin).Thus, very little has changed and first-line and in part second-line drugs have remained the same for decades, in spite of the generally unsatisfactory effectiveness of traditional antiepileptic drugs, the little evidence to support the use of any of them over the other  and the Unfortunately, these notions on pathophysiological peculiarities of developing brain have not yet been translated into a change in clinical practice due to the lack of robust evidence in human newborns. Theoretically bumetanide use seems the most promising strategy, due to its mechanism of action being specifically directed against NKCC1, which is developmentally expressed and responsible of GABA-mediated excitation in the newborn animal brain . The resMoreover, in the context of pyridoxine-dependent epilepsy, innovative strategies like anti-sense therapies have been recently proposed, resulting in normal splicing processes and functional proteins in a sequence and dose-dependent fashion . Future The use of some of the “newer” already available antiepileptic drugs has become wider in clinical practice, although off-label, and their results are described in case series. The main examples include levetiracetam and topiramate, which display favourable pharmacokinetic profiles and alternative mechanisms of action which could positively affect tolerability and efficacy in the neonatal period . The autFor the time being, data on topiramate pharmacokynetics in normothermic neonates are scanty. This issue, together with the unavailability of an intravenous formulation  has resuIn their systematic review, Slaughter and colleagues decided not to directly address the issue of seizures due to metabolic disorders, thus excluding articles with a primary focus on these conditions. They nevertheless include consideration of a pyridoxine trial in their treatment algorithm after second-line medications failure . We suggFurthermore, the issue of a possible impact of gestational age was not addressed, reflecting both the lack of clinical trials on this topic and the current clinical practice, which does not distinguish between term and preterm neonates , even ifAmong term newborns with moderate-to-severe hypoxic-ischemic encephalopathy, therapeutic hypothermia is now posing additional questions regarding neonatal seizures therapeutic options. Detailed data on pharmacodynamics and pharmacokinetics of antiepileptic drugs in hypothermic newborns are needed to enable correct prescription, and have been recently investigated in papers focusing on phenobarbital , lidocaiFinally, a great effort has been made to improve medical management of neonatal seizures in different clinical settings, according to varying professional, instrumental and therapeutic resources ,26. ProtIn summary, although phenobarbital still remains the first-line choice, the use of drugs with alternative mechanisms of action and the avoidance of neurotoxic compounds should be preferred, with the potential to positively impact on neurodevelopmental outcome. Hopefully innovative, efficacious treatment approaches will become available in the near future, as recent studies have mostly focused or will more likely focus on newer antiepileptic drugs.Moreover, the establishment of dedicated protocols for preterm versus term and for normothermic versus hypothermic babies and continuous implementation of protocols for poor-resource settings is warranted to improve timely control of neonatal seizures.


Current scholarly publications heavily rely on high quality peer review. Peer review, albeit imperfect, is aimed at improving science writing and editing. Evidence supporting peer review as a guarantor of the quality of biomedical publications is currently lacking. Its outcomes are largely dependent on the credentials of the reviewers. Several lines of evidence suggest that predictors of the best contributors to the process include affiliation to a good University and proper research training. Though the options to further improve peer review are currently limited, experts are in favor of formal education and courses on peer review for all contributors to this process. Long-term studies are warranted to assess the strengths and weaknesses of this approach. Current scholarly publications visible in most prestigious indexing and citation tracking databases heavily rely on high-quality peer review ,2. The wScience, Nature, Cell, and some other top-tier general medical journals , it was also shown that adding a statistical reviewer substantially increases the quality of manuscripts  quality comments . Anotheruscripts , while auscripts .In addition to the available evidence-based criteria of best reviewers, there are empirical, partly human factors determining the choice of reviewers and the reliance on their recommendations for publication. A large study on author- vs editor-suggested reviewers in a set of leading biomedical journals found no difference in the quality of the reviewer comments while it also advised against the blind reliance on the final recommendations made by author-suggested experts . FurtherThe question arises as to whether there are options to tackle substandard and biased peer review? Training has long been viewed as a potentially useful option. Initial evidence on training points to the fact that short training packages may improve only some aspects of peer review, necessitating evaluation of longer-term interventions . FurtherCurrently most professionals enhance their reviewer skills by learning from more experienced colleagues. In their attempt to improve peer review, some publishers facilitate this option by making reviewer comments open to the authors and reviewers, and by switching toward open-to-public peer review . Not surTraditional and newly launched learned associations may also take the lead in educating authors, reviewers, and editors alike. Fortunately, most of these associations are active in arranging conferences and short courses addressing a range of issues in science writing, editing, and indexing . It is hAcknowledgment The issues presented in the essay were discussed at a Continuous Professional Development (CPD) meeting at Clinical Education Centre of the Russell’s Hall Hospital, Dudley Group NHS Trust (A Teaching Trust of University of Birmingham), Dudley, UK. The authors thank all participants of the meeting for their comments and valuable suggestions.


Treatment for Post-Traumatic Stress Disorder (PTSD) is not always effective, and as the increasing demand for better management of PTSD and combat-related PTSD (CR-PTSD) infiltrates the UK media, so does a pressing need to understand individual variance in disease aetiology. Recent research in psychology, neuroscience and genetics has separately investigated how and why PTSD affects individuals differently. Here, we report on research on trauma, spatial processing and genetics to demonstrate that the hippocampus, part of the medial temporal lobe, is key to understanding how genes and environment interact to determine susceptibility to, and successful recovery from, PTSD. We argue that the integration of these research disciplines will bring new possibilities for prevention and treatment of PTSD within the Ministry of Defence (MOD), emergency services, National Health Service (NHS) and beyond.Individual variations within (CR-)PTSD are a challenge for PTSD research and for treatment approaches. For example, overall lifetime prevalence of exposure to traumatic events varies between 40 and 90% PTSD prevalence and treatment success remain widely unknown  are related to hippocampal activity  in the hippocampus, which is a putative marker of neural integrity , the frequency of met/met genotypes was nearly three-fold higher than in the controls, and the frequency of val/met genotypes was two-fold higher in individuals with probable-PTSD than in controls. The frequency of the BDNF val66met genotypes was significantly higher in those with PTSD and in those with exaggerated startle (a core symptom of PTSD) than in non-PTSD groups. Overall, the val66val genotype has been suggested to increase PTSD resilience, while the val66met allele increases vulnerability of PTSD  will have lower success rates in val/met heterozygotes and met/met homozygotes than in val/val homozygotes, especially if individuals have been exposed to early life stress. This is because spatial contextualization is dependent on hippocampal processing, and hippocampal integrity and plasticity is mediated by the val66met BDNF polymorphism.In conclusion, we suggest that genetic analysis can help to predict the success of different types of PTSD treatments and methods of trauma processing, and may be used to improve referral pathways and eventually PTSD recovery rates.Research between UCL, Bournemouth University, the NHS and Combat Stress is currently being undertaken to quantify the relationship between the BDNF gene, combat and childhood trauma processing and hippocampal-dependent navigation, with the intention of providing new insight into the experience of PTSD in the UK.


There are several statistical process control (SPC) methods used in industry that can be applied in healthcare. However, as noted in the earlier discussion by Toulany et al. regarding quasi-experimental designs for quality improvement research, several considerations must be taken into account when adapting these methods for the complex, high-risk healthcare arena. Industrial methods should be adjusted for (a) heterogeneity at the patient level, including illness type, individualized care, and demographics, (b) heterogeneity at the process level, including geographical and longitudinal clinical care variation, (c) lack of pre-existing standards of comparison for new products or processes, and (d) the critical difference between statistical variation and acceptable clinical risk. Potential methods for successful adaptation of industrial SPC methods for healthcare monitoring and improvement include (a) converting periodic data into cumulative charts to increase detection of trends and (b) addressing heterogeneity through risk adjustment, using a prediction model or propensity score matching. These adjustments tend to inflate Type I errors, however, due to repeated measurements. Thus, the Sequential Probability Ratio Testing (SPRT) method may be of particular use . SPRT usIndustrial SPC methods assume process homogeneity and that the outcome rate from the population establishes the threshold for detecting changes in the process. Using these techniques to analyze processes in healthcare often requires addressing the risk and complexities inherent in healthcare in order to obtain meaningful results. As with any data-driven project, the clinical question and limitations of the available data drive the selection of the patient cohort, SPC method, risk adjustment framework, alerting thresholds, and the interpretation of clinical significance. However, regardless of the SPC method used and the risk-adjustment framework, it is important to realize that performance of the risk adjustment model drives the overall result; thus understanding the strengths and weaknesses of each particular model is critical to clinical interpretations. In addition, detecting adverse outcomes over a long period requires recalibrating the model over time to adjust for systematic changes in clinical care. Finally, all signals detected using these methods require root cause analyses (RCA) and sensitivity analyses as they are hypothesis-generating, not confirming.The use of time series and risk-adjusted control charts are increasingly common methods of presenting and analyzing data related to quality improvement initiatives. Once the domain of industries that were concerned with consistent performance and production of mechanical outputs, SPC techniques are now being used to monitor clinical outcomes, benchmark data in quality registries, and provide surveillance of new medical products and adverse events. Despite the large amounts of data that are often analyzed, the near-real time surveillance of outcomes using these techniques allows quick detection of special cause variation. In turn, interpretation of special causes may result in quick identification of clinically meaningful efficacy or conversely, concerning signals that safety is at risk. After a negative special cause is detected, an RCA can be used to identify likely risk factors and determine the real signal of interest requiring amelioration amongst the clinical and statistical noise. For example, SPC techniques in combination with an RCA were used to identify a link between retroperitoneal hemorrhage and using vascular closure devices with high femoral access in percutaneous coronary interventions. This finding was used to prompt educational interventions and modify clinical practice .Multiple sources of data are available for conducting quality improvement research or initiatives utilizing SPC techniques, both locally and on a large scale. These sources include electronic medical records (EMRs), regional and national data registries, and clinical trial registries. Additionally, the appropriate SPC method can be used both for relatively rare events and for more frequently occurring events, increasing their utility for a range of settings and outcomes of interest.Thus increasing sophistication and adaptation of proven industrial SPC methods, particularly in terms of risk-adjustment and measurement of rare outcomes, have provided additional tools to both those conducting local quality improvement initiatives and investigators who rely on the validity of quality registries to conduct research. This has the potential to increase the immediate clinical impact of quality improvement work as well as the dissemination of interpretable data and research findings. These methods are increasing in use within the healthcare domain, but remain an open area of methodology research as some complexities of healthcare data, such as repeated measurements of the same patient or institution, require further adaptation of these methods.There are four key requirements and recommendations for making greater use of these SPC methods. First, additional infrastructure for collecting valid and reliable data is needed. The data required to drive these methods is facilitated by the structured data entry and collection from the EHR. This may include building basic EHR infrastructure; greater interoperability between EHRs; restructuring of EHRs, including templates for capturing specific variants; and greater use of natural language processing to capture potentially relevant details from free text and dictated notes. Second, collaboration between statisticians, registry experts, healthcare informaticists, and clinicians is required to address the complexity and heterogeneity inherent in data registries. The expertise of each is needed to extract, risk-adjust, and interpret the data required for answering the right question in an understandable way. Third, the limited amount of funds available to improve data infrastructure, support expertise, and collect and maintain the necessary data may necessitate restructuring of the payment system, potentially at both the state and national level. Because all payers, as well as patients and healthcare facilities, benefit from improved care, new methods of sharing savings and reforming payments could support advancement of these methods. Finally, as SPC methods continue to evolve and the infrastructure needed to support them grows, use of key techniques such as time-series and risk-adjusted control charts should be integrated into the clinical and graduate education of healthcare professionals, assuring their availability and accessibility for healthcare improvement.


Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy. Hepatic encephalopathy (HE) is a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain diseases . It can Symptoms of overt HE are reported in approximately 30–45% of patients with liver cirrhosis and 10–50% of patients with transjugular intrahepatic portosystemic shunts (TIPS) . IncidenPredisposing factors for the development of HE are alcohol consumption, high levels of ammonia, zinc and branched chain amino acids, the presence of esophageal varices, and MHE . ElectroPatients with HE can present a number of clinical symptoms, which intensity increases with the progress of HE, such as: changes in personality, impaired sleep-wake cycle, attention, concentration, cognitive, and motor functions, such as psychomotor slowing, asterixis , 13, 14.According to previous studies, hyperammonemia is the main factor responsible for the brain abnormalities in HE , 17. SevAmmonia is a major substrate for a number of enzymatic reactions in the brain and is also a product of some other reactions . ChildreAmmonia influences also other mechanisms leading to development of hepatic encephalopathy such as: impaired blood-brain barrier, changes in neurotransmission, proinflammatory cytokines, oxidative stress, abnormalities in GABA-ergic or benzodiazepine pathways, impaired energy metabolism of the brain, and impaired cerebral blood flow , 25–27.Blood-brain barrier (BBB) is formed by the endothelial cells that line cerebral microvessels , 28. BBBAmmonia is a neurotoxin responsible for HE development via a direct effect on the metabolism and functions of the CNS and influencing the passage of various molecules across the blood-brain barrier, transport of branched chain amino acids, and aromatic amino acids (AA), which inflow is increased due to the formation of Gln in the process of ammonia detoxification .Disturbances of AA transport affect the brain catecholamine synthesis (serotonin and dopamine) and the production of “false neurotransmitters” (octopamine and fenylethylamine), resulting in impaired GABA-ergic, serotonergic, and glutamatergic neurotransmission , 25.In the acute liver failure (ALF), which can be the result of hepatotropic viral infection or toxic injury, liver detoxification function is abruptly reduced due to the massive necrosis of hepatocytes. This leads to the hyperammonemia and development of HE, characterized by rapid progression of symptoms from discrete changes in mental status to stupor and coma.Neuropathological studies revealed that the main cause of death in ALF was cerebral herniation with brain edema as the result of astrocyte swelling –36.Pathogenesis of astrocytes swelling in the ALF is not fully understood. Hyperammonemia, brain congestion, inflammation in brain tissue, and systemic inflammatory response play an important role in astrocyte swelling . At the A number of animal studies evaluating blood-brain barrier integrity in the ALF have been carried out. The results indicate a multifactorial mechanism of encephalopathy and cerebral edema, in the pathogenesis of which the blood-brain barrier impairment is essential –43.There are much less research on this subject carried out in humans.Tofteng and Larsen using cerebral microdialysis technique studied biochemical changes in the brain of the patient with ALF during liver transplantation . They shKato et al. examined brain biopsies of 9 patients who died of ALF using scanning electron microscopy and showed the presence of changes indicating that cytotoxic mechanism with cellular edema seems to be the main cause of the brain edema . VasogenKumar et al. analyzed the influence of arterial hyperammonemia on complications and outcomes in a group of 295 patients with ALF . They foAccording to Albrecht et al. in HE associated with chronic liver disease, there is an imbalance between excitatory and inhibitory neurotransmission . Predomiγ-aminobutyric acid (GABA) is another factor increasing inhibitory neurotransmission through various mechanisms: increased levels of endogenous benzodiazepines, increased availability of GABA at GABA-A receptors due to enhanced synaptic release of the amino acid, direct interaction of increased level of ammonia with the GABA-A-benzodiazepine receptor complex, and ammonia-induced upregulation of astrocytic peripheral benzodiazepine receptors (PBZR) [s (PBZR) .Another hypothesis assumes that the HE can be due to the inhibition of the complex GABA-benzodiazepine receptor by benzodiazepine-like ligands, that have high affinity for these receptors . This thHyperammonemia may also be responsible for the increase of neurosteroids concentration , 50. In Ahboucha et al. demonstrated increased concentration of allopregnanolone strong inhibiting neurosteroide that stimulates mitochondrial peripheral-type benzodiazepine receptors (PTBR) in the brain of patients with HE . The eleHyperammonemia may also have a direct toxic effect on the membranes of neurons . StudiesκB (NFκB), activated by oxidative stress, in ammonia-induced astrocyte swelling. The activation of NFκB was associated with increased inducible nitric oxide synthase (iNOS) protein expression and the subsequent generation of nitric oxide (NO) [Study of Sinke et al. on astrocyte cultures proved involvement of nuclear factor ide (NO) .According to Nörenberg et al., oxidative stress induced by ammonia is a major pathogenic factor in the ALF HE pathogenic and causes a whole cascade of events leading to cell swelling and brain edema . HoweverNeuroinflammation is a new element in the pathogenesis of HE described in animal models, which seems to play an important role in the development of cognitive impairment, that can persist after liver transplantation . Shawcross et al. study in patients with liver cirrhosis have shown that inflammation and inflammatory mediators may significantly modulate ammonia influence on CNS (significant deterioration in psychometric test and improvement after the resolution of inflammation) . The infα and IL-6 proinflammatory cytokines in serum of patients with MHE was noticed [A significant increase of TNF- noticed . α, IL-1β, IL-6, and IF-γ and ammonia induce increase of the mitochondria permeability and may be an important factor in the pathogenesis of HE [Alvarez et al. study on the astrocyte cultures indicated that proinflammatory cytokines such as TNF-is of HE . Increased mitochondrial permeability transition results in reduction of ionic gradients and enhance mitochondrial dysfunction, leading to brain energetic disorders that could be a potential target for therapy –67.Ammonia has a neurotoxic effect on brain astrocytes, additionally abnormalities in the cell energetic level and oxidative stress intensify HE. Change of astrocyte mitochondrial membrane permeability under the influence of ammonia and Gln may be an important mechanism for the formation of cerebral disorders associated with HE , 67. NeuAstrocytes, constituing about 1/3 the of the cerebral cortex volume and playing a crucial role in the blood-brain barrier, are involved in maintaining electrolyte homeostasis, remove free radicals, and are responsible for the delivery of nutrients and neurotransmitter precursors to neurons . AstrocyAlzheimer type II astrocytes are found in the gray matter and white matter of the brain and subcortical nuclei and may have various forms suggesting hyperplasia . Number Studies using the electron microscope in an animal model of portosystemic hepatic encephalopathy have shown that astrocytes before coma characterizes increased amount of cytoplasm, proliferation of mitochondria and endoplasmic reticulum, and glycogen accumulation in the cell cytoplasm, while in a coma Alzheimer's type II astrocytes was observed with the presence of degenerative changes in mitochondria and the presence of large pale nuclei with visible nucleoli . These oAnother cause of HE may be dysfunction of neurons as a result of abnormal interactions between neurons and astrocytes and impairment of brain energy metabolism , 67. AmmCerebral energy metabolism and the synthesis of Gln depend on glucose supply to the brain, and the functional activity of the brain depends on the degree of glucose utilization . ChangesYazgan et al. reported significant reduction in blood flow through the thalamus and increase the flow through the frontal lobes of patients with cirrhosis compared with the healthy volunteers . AnotherThe results of research on the role of the local blood flow in the development of MHE are inconclusive.There was also noticed accumulation of toxins in the brain, including manganese, which deposition in the basal ganglia might be the cause of hyperintense signals on T1-images in magnetic resonance imaging (MRI) –79. In pKulisevsky et al. in brain MRI of patients with liver cirrhosis apart from increased signals in the globus pallidus found also brain atrophy, which did not correlate neither with the patients' age nor the disease duration and the number of points in the Child-Pugh score . The posRecently the role of SIBO in the development of MHE has been emphasized , 87.Gupta et al. study demonstrated a high prevalence of SIBO in patients with MHE (38.6%), giving evidence for the prokinetics, nonabsorbable antibiotics and probiotics therapeutic use .Jun et al. found a very high prevalence of SIBO (81.3%) in patients with liver cirrhosis and ascites, which may suggest that SIBO may be a high risk factor for bacterial translocation in patients with ascites .The pathogenesis of HE is complex and so far none of the proposed hypotheses emphasize the role of hyperammonemia and inflammation, and the role of proinflammatory cytokines, impaired neurotransmission, false neurotransmitters, oxidative stress, changes in cerebral blood flow, or brain energy metabolism does not completely explain all associated phenomena.The results of research from last several years show the key role of blood-brain barrier in the development of HE-related disorders, but most of these are animal studies. Therefore, it is necessary to develop some modern diagnostic methods that allow the assessment of human brain metabolism.Better understanding of the encephalopathy pathogenesis in patients with acute and chronic liver insufficiency, early diagnosis of MHE, and new therapies based on this knowledge would prevent the development of overt encephalopathy and neuropsychiatric disorders.