Intensive care units (ICUs) are increasingly adopting 24-hour intensivist physician staffing. Although nighttime intensivist staffing does not consistently reduce mortality, it may affect other outcomes such as the quality of end-of-life care.We conducted a retrospective cohort study of ICU decedents using the 2009–2010 Acute Physiology and Chronic Health Evaluation clinical information system linked to a survey of ICU staffing practices. We restricted the analysis to ICUs with high-intensity daytime staffing, in which the addition of nighttime staffing does not influence mortality. We used multivariable regression to assess the relationship between nighttime intensivist staffing and two separate outcomes potentially related to the quality of end-of-life care: time from ICU admission to death and death at night.Of 30,456 patients admitted to 27 high-intensity daytime staffed ICUs, 3,553 died in the hospital within 30 days. After adjustment for potential confounders, admission to an ICU with nighttime intensivist staffing was associated with a shorter duration between ICU admission and death  and a decreased odds of nighttime death  compared to admission to an ICU without nighttime intensivist staffing.Among ICU decedents, nighttime intensivist staffing is associated with reduced time between ICU admission and death and reduced odds of nighttime death. Intensivist physician staffing is associated with lower mortality and decreased length of stay in the ICU ,2. This Although nighttime intensivist staffing may not reduce mortality in all ICUs, extending intensivist coverage around the clock may have other benefits, including an effect on the quality of end-of-life care. The quality of end-of-life care is an important patient-centered outcome and may be impacted by nighttime intensivist staffing through earlier and more frequent conversations between physicians and surrogate decision-makers regarding prognosis and goals of care . Since iThe purpose of this study was to determine whether nighttime intensivist staffing is associated with the timing of deaths in ICU decedents. We examined two complementary elements of the timing of death: the duration between ICU admission and death, and the odds of death at night. The duration between ICU admission and death is often considered a proxy for the quality of end-of-life care, since reduced hospital and ICU stays for decedents without an increase in overall mortality represents a decrease in ineffective aggressive therapy and prolonged dying . The oddWe performed a retrospective cohort study of ICU decedents using the Acute Physiology and Chronic Health Evaluation (APACHE) clinical information system  from 2009 through 2010. APACHE collects detailed clinical, physiological, and outcome data on adult ICU patients at participating hospitals for benchmarking and quality improvement. The APACHE database has been used for numerous observational studies involving critically ill patients ,15. We lPatients who were 17 years of age or older and admitted to a study ICU were eligible for inclusion in the study. We excluded readmissions, patients admitted to low-intensity ICUs, those who survived to hospital discharge, and decedents whose death occurred more than 30 days after ICU admission. We limited the study to ICUs with high-intensity daytime staffing, for which nighttime intensivist staffing does not affect mortality , to elimThe two primary outcome variables were time from ICU admission to death and odds of death at night (defined as death occurring between 7:00 pm and 7:00 am). These variables were chosen because they may represent proxies for the quality of end-of-life care  and the a priori as potential confounders between nighttime staffing and timing of death based on previous studies [Covariates were specified  studies ,15. Pati studies .t tests for continuous variables and chi-square tests for categorical variables.We compared the characteristics of hospitals with and without nighttime intensivist staffing using the Mann–Whitney test for continuous variables and Fisher’s exact test for categorical variables. We compared patient characteristics between ICUs with and without nighttime intensivist staffing using two-sample Unadjusted time from ICU admission to death was evaluated using Kaplan–Meier curves. Differences in the survivor functions between decedents admitted to ICUs with and without nighttime intensivist staffing were evaluated using the log-rank test.We used multivariable linear regression to assess the relationship between nighttime intensivist staffing and time from ICU admission to death. We chose linear regression of untransformed length of stay over other approaches since it is a valid method for large samples regardless of distribution, including highly non-normal samples of >500 subjects, when the mean value is the outcome of interest . We usedPatient race was missing in 9% of our cohort, and this variable is known to relate to the intensity of end-of-life care for hospitalized patients . To accoa priori selected subgroups with which we hypothesized that nighttime intensivists would interact most frequently, thereby having the largest effect on the timing of death. These subgroups included patients admitted to the ICU at night and two subgroups of patients likely to decompensate overnight due to their increased severity of illness: patients mechanically ventilated on ICU admission and patients with an Acute Physiology Score ≥75 .We performed a number of sensitivity analyses to assess the robustness of our findings. First, we repeated our analyses using ICU length of stay rather than time from ICU admission to death, since the time from ICU admission to death may be affected by the timing of transfer out of the ICU for patients ultimately dying on the ward. Second, we repeated the time to death analysis considering patients discharged to a hospice as decedents, since the decision to die in the hospital versus a hospice may be affected by patient and surrogate preferences. Third, we examined the effect of nighttime intensivists on the odds of death at night using a second definition of death at night (8:00 pm to 8:00 am) in order to account for the time delay between withdrawal of life-sustaining therapy and death .P ≤0.05 was considered significant. This research was approved by the Institutional Review Board of the University of Pittsburgh. A waiver for individual informed consent was provided due to the minimal risk for participants.All statistical analyses were performed using Stata 12.0 . All tests were two tailed and P = 0.78) [The initial cohort included 64,752 admissions to 49 ICUs in 25 hospitals. A total of 3,553 decedents admitted to 27 high-intensity daytime staffed ICUs in 15 hospitals met the study inclusion criteria .Characteristics of the 3,553 decedents in the study are shown in Table In the multivariable analysis, we found that adjusted length of time from ICU admission to death was significantly shorter among decedents admitted to ICUs with nighttime intensivists compared with those without Table . This waIn a retrospective cohort study of decedents admitted to high-intensity daytime staffed ICUs, the presence of a nighttime intensivist was associated with a decrease in time from ICU admission to death by an average of 2.5 days. This finding suggests that the addition of nighttime intensivists to high-intensity daytime staffed ICUs may improve the quality of end-of-life care for ICU decedents. A possible mechanism may be earlier and more frequent conversations between intensivists and surrogates regarding prognoses and goals of care, leading to earlier withdrawal of life-sustaining treatment. Nighttime intensivist staffing may improve both the timing of communication with surrogates and surrogates’ access to physicians, which research suggests are two aspects of end-of-life care in need of improvement . As a reContrary to our hypothesis, we found that the addition of a nighttime intensivist to high-intensity daytime staffed ICUs was associated with decreased odds of death at night. Although nighttime intensivist staffing may lead to earlier withdrawal of life-sustaining treatment, this finding suggests that it is unlikely to be occurring more frequently at night. Instead, nighttime intensivists may have discussions with surrogates preparing them for withdrawal of life-sustaining treatment by the daytime team. Additionally, the decreased odds of death at night may indicate that nighttime intensivists are better able to manage decompensating patients overnight than non-intensivists, forestalling death in the short term. Fewer deaths at night may allow more family members to be present at the time of life-sustaining treatment withdrawal and patient death, further supporting the notion that nighttime intensivists may improve the quality of end-of-life care for ICU decedents .Our findings have implications for the many ICUs that have already implemented nighttime intensivist staffing or those that are considering implementing nighttime staffing. A relationship between nighttime intensivists and the quality of end-of-life care for ICU decedents may provide a rationale for the continuation or implementation of the nighttime intensivist ICU staffing model, even in the absence of a mortality benefit. Additionally, the reduction in time between ICU admission and death represents decreased resource utilization.Our study has several limitations. The hospitals in this study were a self-selected group of hospitals participating in the APACHE clinical information system rather than a random sample. Compared with other hospitals in the United States, APACHE hospitals are generally larger and more likely to be affiliated with an academic institution. Therefore it is not known whether the findings in this study would be applicable to all other high-intensity daytime staffed ICUs. Second, we acknowledge that confounding by unmeasured ICU characteristics may have affected our results. For example, ICUs with nighttime intensivist staffing may have different norms regarding the use of time-limited trials of life-sustaining treatment for patients than ICUs without nighttime intensivist staffing; this could be an alternate explanation for the reduced time between ICU admission and death. Third, we did not directly measure the quality of end-of-life care; we used a proxy. We acknowledge that there is limited evidence regarding the relationship between timing of death and the quality of end-of-life care, and that a shorter duration between ICU admission and death may not be associated with higher family satisfaction in all cases . Future Among ICU decedents, the addition of nighttime intensivist staffing to high-intensity daytime staffing is associated with a reduced time between ICU admission and death and reduced odds of death at night.• Among decedents admitted to high-intensity daytime staffed ICUs, the addition of a nighttime intensivist was associated with a reduced time between ICU admission and death.• Among decedents admitted to high-intensity daytime staffed ICUs, the addition of a nighttime intensivist was associated with reduced odds of death at night.• The addition of nighttime intensivist staffing to high-intensity daytime staffed ICUs may improve the quality of end-of-life care.APACHE: Acute physiology and chronic health evaluation.The authors declare that they have no competing interests.LAR contributed to the study design, performed analysis and interpretation of the data, and drafted the manuscript. DJW contributed to the analysis and interpretation of the data and revision of the manuscript. AEB contributed to the analysis and interpretation of the data and revision of the manuscript. JMK conceived the study and study design, assisted in the analysis and interpretation of the data, and revised the manuscript. All authors read and approved the final manuscript.LAR is a pulmonary and critical care fellow at the University of Pittsburgh. DJW is an Assistant Professor of Critical Care Medicine and Emergency Medicine at the University of Pittsburgh. AEB is an Associate Professor of Medicine, Clinical and Translational Science, and Health Policy & Management at the University of Pittsburgh. JMK is an Associate Professor of Critical Care, Medicine, and Health Policy & Management at the University of Pittsburgh.presenting results of sensitivity analyses comparing ICUs with versus without nighttime intensivists.Click here for file


Service delivery innovation is at the heart of efforts to combat the growing burden of chronic disease and escalating healthcare expenditure. Small-scale, locally-led service delivery innovation is a valuable source of learning about the complexities of change and the actions of local change agents. This exploratory qualitative study captures the perspectives of clinicians and managers involved in a general practitioner-led integrated diabetes care innovation.Data on these change agents’ perspectives on the local innovation and how it works in the local context were collected through focus groups and semi-structured interviews at two primary health care sites. Transcribed data were analysed thematically. Normalization Process Theory provided a framework to explore perspectives on the individual and collective work involved in putting the innovation into practice in local service delivery contexts.Twelve primary health care clinicians, hospital-based medical specialists and practice managers participated in the study, which represented the majority involved in the innovation at the two sites. The thematic analysis highlighted three main themes of local innovation work: 1) trusting and embedding new professional relationships; 2) synchronizing services and resources; and 3) reconciling realities of innovation work. As a whole, the findings show that while locally-led service delivery innovation is designed to respond to local problems, convincing others to trust change and managing the boundary tensions is core to local work, particularly when it challenges taken-for-granted practices and relationships. Despite this, the findings also show that local innovators can and do act in both discretionary and creative ways to progress the innovation.The use of Normalization Process Theory uncovered some critical professional, organizational and structural factors early in the progression of the innovation. The key to local service delivery innovation lies in building coalitions of trust at the point of service delivery and persuading organizational and institutional mindsets to consider the opportunities of locally-led innovation.The online version of this article (doi:10.1186/s12913-016-1270-4) contains supplementary material, which is available to authorized users. Characteristically, healthcare innovations relate to emergent health technologies, new products and services, and altered processes of service delivery –3. The rService delivery innovations emerge through different approaches. Top-down policy-driven approaches aim for large-scale system-wide change and are often accompanied by changes to funding arrangements or other financial or performance incentives. For example, the Australian government introduced Medicare items to encourage general practitioners (GP)s to develop coordinated care plans and team care arrangements for patients with chronic disease , 6. LikeService delivery innovations that integrate specialist care with primary health care services are increasingly preferred to deliver quality and cost effective care for patients with chronic disease . LikewisFrom the evidence established to date, service delivery innovations integrating specialist services in primary care are highly dependent on the commitment of clinicians and their extent of collaboration , 29. UnsA GP-led integrated diabetes care innovation was developed in Queensland, Australia to provide diabetes care to patients with complex, unstable diabetes who would otherwise visit a consultant-led hospital outpatient clinic for their diabetes management. Unacceptably long waiting lists for hospital clinics and the belief that with adequate training and support, GPs could provide the required high quality care for people with diabetes underpin the model of care. In this GP-led model, complex diabetes care is provided in the community by a co-located multidisciplinary team comprising an endocrinologist, advanced-skilled GPs , a credentialed diabetes educator and a podiatrist; with access to other allied health staff on referral depending on patient need. Clinical fellows are experienced local GPs who have undertaken additional postgraduate education in advanced diabetes care. The patient’s referring GP is kept closely informed of all care management and patients are discharged back to them once clinical targets are achieved or after 12 months if it is felt no further improvement can be achieved. The key components and process of care related with this integrated model of diabetes care are fully described elsewhere .In this paper, we report on focus groups with medical and non-medical primary health care professionals and interviews with hospital-based specialists and managers about their perceptions and experiences of a GP-led integrated diabetes care innovation in primary health care. In this case, we were interested in exploring their experiences with an emergent small-scale local innovation to understand the complexities of local innovation work and to inform a broader implementation strategy. The broad aims were to capture multiple perspectives on: a) the meaning and value of the new model of service delivery in the local context; b) the acceptability and compatibility of the new model, with reference to professional relationships, teamwork and organizational capacity; and c) factors likely to impact on local change processes.A qualitative research design incorporating focus group meetings and semi-structured interviews was employed to explore the perceptions and experiences of primary health care professionals, hospital-based medical specialists and practice managers involved in a GP-led integrated diabetes care innovation. Using both focus groups and interviews enabled the views of participants in diverse roles to be captured within the data collection timeframe. The focus groups and interviews formed part of a larger mixed method evaluation of integrated primary-secondary care for complex diabetes care in the primary health care setting. Using a randomized control trial , eligiblThe qualitative study was informed by Normalization Process Theory (NPT). The value of NPT is that it focuses on the meaning that agents of change attribute to new innovations and the work that they do individually and collectively to implement and embed the innovation in day-to-day practice . From thPrimary health professionals, hospital specialists and practice managers participating in the implementation of the GP-led integrated diabetes care were purposively recruited from two of the three sites where the innovation had been established for at least six months. The third site was established more recently and as such is not included in the analysis. Potential participants were contacted by phone and in writing by one of the researchers (LB) with information about the study and invited to participate in either a focus group or an interview. Twelve participants were recruited across the two sites, including eight primary health care (PHC) clinicians, and two hospital-based endocrinologists and two practice managers (henceforth referred to as stakeholders). Importantly, the sample included all those directly involved with the local innovation in the two sites, with the exception of four PHC clinicians who were unavailable at the time of data collection due to work commitments. In one site, five PHC clinicians participated in focus group discussions and two stakeholders were interviewed (one endocrinologist and one practice manager). In the second site, four clinicians were recruited for the focus group. However, one did not attend on the scheduled day due to work commitments. Two stakeholder interviews were also completed in this site. A description of participants is shown in Table In each site, focus groups and interviews were conducted approximately six months after commencement of the GP-led integrated diabetes service. To ensure consistency across focus groups and interviews, a topic guide was developed, incorporating key topics and open-ended questions linked to the study aims and conceptual ideas of NPT  trusting and embedding new professional relationships; 2) synchronizing services and resources; and 3) reconciling realities of innovation work ].Equally, participants across both sites recognized the work in changing a system mind set. For some PHC and stakeholder participants there was a sense of individual responsibility to drive change in the local context. For one participant, the locally-led integrated care innovation was difficult work because of minimal interest, and consequently, this elevated individual responsibility for generating ideas about new ways of service delivery and bringing consensus in the local context.aiming for the same outcome [S4]. The PHC participants and specialist stakeholders also reinforced the necessity of local leadership to engage and convince the various stakeholders across all levels of the system. One participant clearly brought to light the challenge of changing an organizational and institutional mindset historically framed on the values of autonomy and tradition.You have clinicians, clinician engagement and nursing engagement in a general practice. The key thing will be engaging of the clinician. Because general practice is very autonomous you need to have everyone onside and behind it. Change is hard. People are resistant. Medicine is particularly resistant to change. Getting them to hand over certain things, change behaviours, submit to audit, all that sort of stuff is challenging. If you can get everyone engaged in that process then it is very exciting, success breeds success [C4]Similar to bringing local people around, there was an appreciation of the work required to gain consensus across all disciplines to ensure everyone is This theme accentuates the realities of emergent tensions in innovation work across micro-level, organizational and healthcare system boundaries. It is insightful about the pivotal roles that front-line clinicians occupy in managing these boundaries. The critical roles of change champions and boundary navigators are evident, as is the weakness of locally-led innovation if these people are lacking. Consequently, this theme also uncovers the potential risks to the progression and legitimacy of locally-led service delivery innovations.This exploratory study on a GP-led integrated diabetes care innovation in primary health care captured the perceptions and experiences of primary health professionals, hospital specialists and practice managers. The findings as a whole provide further insight into the professional and organizational aspects of local change work . More soA further consideration relates to the importance of organizational and health system factors to the evolution and progression of a professionally-led local innovation, confirmed in the second and third themes. Unlike some innovations that are highly contained to micro-level changes in professional practice , this GPImportantly, as the findings suggest, this bottom-up locally-led service delivery innovation represents a novel process innovation  in this This study provided an opportunity to rigorously evaluate an emergent bottom-up service delivery innovation, drawing on clinicians’ and managers’ perspectives. However, the findings must be interpreted within the limitations of the study. In this case, the study involved two sites and 12 participants, though this included the majority of those directly involved in ongoing small-scale local innovation work. Although the findings provide valuable insights into an emergent small-scale local innovation, the findings are not transferable to other settings. On the other hand, the application of NPT allowed an exploration of the nuances of individual and collective work to progress the innovation, from multiple perspectives across clinical and organizational levels. Though this is limited to a small-scale innovation within specific contexts, nonetheless, the theory is valuable in eliciting the dynamic conditions and dimensions of innovation work for focus in formal evaluation . Future This study contributes much needed knowledge about the complexities of locally-led service delivery innovation. Although the micro-level innovation work is often complicated by organizational and broader systemic factors, nonetheless, innovators can and do act internally and externally, and proactively, to progress the innovation. However, the key lies in building consensus and coalitions of trust at the point of service delivery and longer-term persuading organizational and institutional mindsets to consider the opportunities of locally-led service delivery innovation.


An understanding of differences in hospital costs between patient groups is relevant for the efficient organisation of inpatient care. The main aim of this study was to confirm the hypothesis that eight a priori identified cost drivers influence per diem hospital costs. A second aim was to explore further variables that might influence hospital costs.The study included 667 inpatient episodes consecutively discharged in 2014 at the psychiatric hospital of the Medical Centre- University of Freiburg. Fifty-one patient characteristics were analysed. Per diem costs were calculated from the hospital perspective based on a detailed documentation of resource use. Mixed-effects maximum likelihood regression and an ensemble of conditional inference trees were used to analyse data.The study confirmed the a priori hypothesis that not being of middle age (33–64 years), danger to self, involuntary admission, problems in the activities of daily living, the presence of delusional symptoms, the presence of affective symptoms, short length of stay and the discharging ward affect per diem hospital costs. A patient classification system for prospective per diem payment was suggested with the highest per diem hospital costs in episodes having both delusional symptoms and involuntary admissions and the lowest hospital costs in episodes having neither delusional symptoms nor somatic comorbidities.Although reliable cost drivers were identified, idiosyncrasies of mental health care complicated the identification of clear and consistent differences in hospital costs between patient groups. Further research could greatly inform current discussions about inpatient mental health reimbursement, in particular with multicentre studies that might find algorithms to split patients in more resource-homogeneous groups. Understanding the differences in hospital costs between patient groups is relevant at different levels of health care systems. This can be decision-making in clinical practice or the efficient allocation of funds at policy level, for instance by the design of reimbursement schemes.A well-designed reimbursement scheme is necessary for the efficient delivery of inpatient care. Inappropriate reimbursement rates can create unintended incentives, such as the reduction of costs at the expense of quality, early discharges to reduce length of stay for pecuniary reasons or to avoid treating high cost patients –3. Thereper case infeasible [Case-mix based reimbursement has gradually become the basis of paying hospitals in most industrialised countries . Such scfeasible . Therefofeasible –11. FurtProspectively defining adequate per diem payments for different patient groups requires an understanding of factors that influence per diem hospital costs. A systematic review has found six patient and two service characteristics that influence per diem hospital costs . HoweverThe aim of this study was to confirm the hypothesis that the eight concepts a priori identified as potential cost drivers in a systematic review  influencThe study included all inpatient episodes (n = 667) discharged in 2014 at the psychiatric hospital of the Medical Centre- University of Freiburg, Germany. An episode was defined as the time from admission to formal discharge. Readmission after formal discharge and the initial episode were treated as an aggregated episode if time away was less than two weeks. Episodes treated at the ward for privately insured patients were excluded because it was not possible to collect all data for these patients. The hospital has eight wards with a total of 120 beds. The study and its methodology were approved by the works council of the Medical Centre-University of Freiburg. The ethics committee of the Albert-Ludwigs-University of Freiburg confirmed that the study did not require formal approval. All data were analysed anonymously.The analyses required both a description of episode-specific patient and service characteristics and episode-specific mean per diem costs. Patient characteristics were derived from the electronic medical records of the psychiatric hospital and from the patient administration database. A total of 51 patient characteristics were investigated. These included the variables from the admission module of the minimum data set recommended by the German Association for Psychiatry, Psychotherapy and Psychosomatics . Furtherage was dichotomised and patients of middle age, meaning 33–64 years, were separated from other patients, since the systematic review identified middle-aged patients to be different from young and old patients. Risk was operationalised with two variables, i.e. danger to self and danger to others, separately. Being admitted involuntarily or by a legal guardian was used to represent the concept of legal problems. Any problems in the dimensions eating, toileting, mobility and hygiene were separately used to represent the performance in activities of daily living. The score for delusional symptoms and the score for affective symptoms on the scale of the Association for Methodology and Documentation in Psychiatry (AMDP) were used to represent the degree of psychotic or affective symptoms independently from each other and from the actual main diagnosis. Furthermore, the aim of this study was to estimate mean per diem hospital costs. Therefore, the concept day of stay, i.e. cost at day one versus cost at day two, etc., was operationalised by the total length of stay of a hospital episode. Moreover, since this study was carried out at a single hospital, the concept treatment site was operationalised by the different wards at the hospital. These wards were led by different head psychiatrists and head nursing staff and were non-exclusively dedicated to different patients groups, such as patients requiring a locked environment, older patients and patients of specific diagnoses.The eight concepts that were identified as potential cost drivers in advance were operationalised in this paper with the aim to be as close as possible to the results of the systematic review  with thePer diem costs were calculated from the hospital perspective. All services a patient received during a stay were valued by their full operating costs to the hospital, i.e. including variable and fixed cost shares. This included all staff, materials, infrastructure and overhead costs at the psychiatric hospital as well as all costs for services from other departments, such as radiology and laboratories. Capital costs were excluded. The sum of costs an inpatient episode incurred was divided by the length of stay to calculate mean per diem costs.Staff time in therapeutic interventions was calculated by multiplying the duration of each intervention with the number of therapists and dividing the product by the number of patients. This included psychotherapeutic interventions, physical therapies, occupational therapies and other measures, such as electroconvulsive therapies.Staff time for regular care, meaning all clinical time except of therapeutic interventions, was calculated in a two-stage approach. First, total staff time in regular care activities was calculated for each ward in a two-week work sampling study including all physicians, nurses and psychologists involved in clinical care during the study period. The applied methods were described in detail elsewhere . Second,The consumption of expensive pharmaceuticals of at least 10 € per daily dosage was extracted from the electronic medical records and valued by their average purchasing price to the hospital’s pharmacy in 2014. Per diem costs for low price pharmaceuticals and other medical products were calculated by dividing the annual sum of such costs at each ward by the total number of patient days at each ward.Ward-specific mean per diem overhead costs, such as buildings, beds, meals and administration, were derived by the iterative step-down allocation method on a cause-and effect basis with per diem charges. Services from other departments, such as radiology and laboratories, were documented by their local clinical sub-systems and valued by department-specific costs.Fourteen per cent of total episodes had incomplete data, i.e. at least one variable missing. Multiple imputations by chained equations were used for the non-monotone pattern of missing data. The imputation model comprised all available independent variables and the outcome variable to prepare the data set for the explorative analysis. Twenty imputations with 50 iterations each were carried out, convergence of iterations was traced and distributions of imputed and observed data were compared.The hypothesis driven analysis of variables previously identified as potentially relevant cost drivers was carried out using mixed-effects maximum likelihood regression. A three-level model was employed, with random intercepts for the individual episode nested within the patient and the patient nested within the discharge ward. The association of length of stay and mean per diem costs was assessed using partial residual plots and locally weighted regressions. The independent variables that were used to represent the eight potential cost drivers were checked in advance for potential multicollinearity with unproblematic results according to common standards   was longer than the average length of stay in psychiatric hospitals in Germany and much longer than in some other health care systems, such as in the USA , 23. In A further weakness was in the daily documented acuity score used to calculate costs of regular care. This score has been developed by the German Institute of Hospital Reimbursement and the German Association for Psychiatry, Psychotherapy and Psychosomatics specifically to represent staff’s effort of regular care . HoweverThe hypothesis-driven analysis mainly confirmed the results of prior research , namely Analyses in previous studies investigated the univariate influence of main diagnoses ,25,26. RThe ensemble of conditional inference trees employed all 51 available patient variables. It explained the variance in per diem costs substantially to moderately in the complete sample (43.5%) and the internal cross-validation (19.4%), respectively. The absolute values of variable importance were neither informative themselves nor comparable to other studies. However, ten variables were identified that yielded substantially higher values than the other and these should constitute a basis for further investigations.Interestingly, the most important variable in the ensemble of trees, the GAF score , was notThe suggested patient classification system of six mutually exclusive and exhaustive groups for payment purpose can be employed with only five documented patient characteristics . Its modThere are three potential reasons for relatively low power of patient variables in predicting mental health per diem resource use. First, there is a wider range of accepted treatment strategies and therefore less standardisation of care ,27. ThisInappropriate hospital reimbursement can create unintended provider incentives and inefficient delivery of care –3. The aS1 FigAMDP = Association for Methodology and Documentation in Psychiatry, CGI = Clinical Global , Impress(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.


Ictal kissing has been described in the literature. Five cases were reported and associated with temporal lobe epilepsy lateralizing to the nondominant hemisphere.A case of ictal kissing was identified. The aim was to demonstrate the clinical, clinical and electrophysiological features . The surgical procedure, histopathology, and imaging data were reviewed and correlated with the literature.A 29-year-old right-handed female, who presented with ictal right hand left arm dystonic posturing, and lip smacking, was studied. The automatism was usually followed by prolonged emotional gestures and by hugging and kissing her relative and/or attendant nurse. Magnetic resonance imaging of the brain showed right small cortical and subcortical lesions of the right inferior frontal lobe with gliosis but without mass effect and normal-sized hippocampi. The PET scan showed hypometabolism of the right temporal lobe. Neuropsychological evaluation showed deficit in her nonverbal memory. The subdural electrodes showed high amplitude spikes over right mesial temporal lobe strips. The offsite of the ictal discharges was usually at the right frontal strips. Right standard temporal lobectomy with amygdalohippocampectomy and right inferior frontal lesionectomy were performed. The patient continued to be seizure-free for one year postoperatively.Our case report supports with subdural EEG recording the findings of the few reported cases of ictal kissing behavior lateralized to the nondominant hemisphere. However, the affectionate kissing behavior was associated with spread of the epileptic discharges to the right frontal lobe. The patient has no history of febrile convulsions. She has a history of an aura of fear followed by automatism consisting of right hand left upper limb dystonic posturing, and lip smacking. The automatism was usually followed by prolonged emotional gestures, hugging and kissing her relative and/or attendant nurse. The patient's seizure frequency varied from 1 to 2 per month. Magnetic resonance imaging of the brain showed small cortical and subcortical lesions of the right inferior frontal lobe without mass effect or enhancement. The lesion was located directly anterior of the insular gyrus and inferior to the inferior frontal gyrus . The hip3In the Epilepsy Unit, 5 push button events were recorded. The subdural electrodes showed clinical correlation of fear and palpitation with an onset of high amplitude spikes over right mesial temporal lobe strips  , neuroscientists have demonstrated increased interest in the neurobiology and neurochemistry of emotions, including love and affection Few fMRI studies elucidating neural correlates of romantic and affection have been published In conclusion, our findings support the idea that the ictal kissing behavior is a phenomenon of nondominant temporal lobe epilepsy. However, it is possibly linked to a circuit involving regions beyond the temporal lobe, such as the medial insula, anterior cingulate cortex, medial orbitofrontal, and hippocampus in the nondominant hemisphere.


Pseudoachalasia is a rare disorder whose presentation strongly resembles idiopathic achalasia.Here, we present a case of a 42-year-old female patient with esophageal leiomyoma who was initially diagnosed with achalasia. On endoscopical investigation, however, it became apparent that she had pseudoachalasia as consequence of a leiomyoma at the esophagogastric junction (EGJ). The condition was successfully treated through submucosal tunneling endoscopic resection.This case suggests that submucosal tunneling endoscopic resection is a therapeutic u option for the treatment of pseudoachalasia caused by leiomyoma of EGJ. Achalasia is the most common functional gastrointestinal disorder. It is characterized by aberrant upper gastrointestinal motility due to loss of peristalsis in the lower two-thirds of the esophagus and impaired relaxation of the lower esophageal sphincter , 2. AchaA 42-year-old female patient was referred to the Department of Gastroenterology at the Second Clinical College of Yangzhou University, for long-standing complaints of solid and liquid dysphagia accompanied by episodes of regurgitation. She underwent two upper digestive endoscopies, on which the presence of food residues in the esophageal lumen and rebound passage through the gastroesophageal junction was observed. Gastroesophageal contrast radiography showed slight dilatation of the esophagus, an absence of primary peristalsis but presence of aperistaltic waves, and a narrow distal esophagus with a ‘bird’s beak’ aspect Fig. . A CT scAchalasia is a primary esophageal motility disorder, which manifests itself through dysphagia to liquids and solid foods. Support for a diagnosis of achalasia can be obtained by endoscopic and radiological studies, but the mainstay of the diagnostic process consists of the manometric findings. Classically, three characteristic manometric features are present in achalasia: an elevated resting lower esophageal sphincter pressure, incomplete lower esophageal sphincter relaxation, and esophageal aperistalsis . PseudoaPOEM is a novel endoscopic technique for the treatment of achalasia. Since Inoue et al.  reportedWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor in Chief of this journal. This study was reviewed and approved by the Institutional Review Board of Second Clinical College of Yangzhou University.


Dear Sir,The lack of external nose is generally a part of the complex malformation characterized by the absence of the nasal cavities, microphthalmia or coloboma of olfactory bulbs, high arched palate, coloboma of iris, and microtia. Only 43 cases of arhinia have been reported to date [1-4].A healthy 40-year-old, gravida 5 and para 5, woman delivered a male infant weighing 2.89 kg by spontaneous vaginal delivery at term. There was neither a family background of congenital malformations nor a history of any medications during the pregnancy. The prenatal course was uncomplicated. On examination, the baby showed absence of the nose, nasal root, nasal pits; microphthalmia, auris dextra microtia, right side anorchia, small penis, high arched palate, hypoplasia of bilateral maxillary sinus and ethmoid sinus . There were longitudinal ridge-like protuberances in the mid-face. Shortly, the infant was transferred to the neonatal intensive care unit for further evaluation and monitoring. The baby had severe shortness of breath which was relieved by an oropharyngeal tube. Karyotyping performed was 46 XY. The dyspnea and tachypnea greatly improved one month later and the baby adapted to oral breathing and feeding simultaneously. Further work-up including echocardiogram, CT brain, and blood chemistry, all were normal. The embryogenesis of nose occurs between the third to eighth week of life. Two fast growing ridges  develop in the fifth week, forming the medial and lateral nasal swellings and giving rise to the nasal pits between the swellings. The medial swellings fuse to form the nasal septum. Cells within the nasal pits continue to migrate posteriorly to form the primitive nasal cavities, which are separated from the buccal cavity by the rudimentary palatal shelves. It is postulated that lack of development of the nose results from medial failure and lateral nasal process growth, but it is also possible that overgrowth and premature fusion of the nasal medial process result in the formation of an atretic plate . Several genes involved in the nose and facial development have been recognized, however, no consistent gene mutations have been discovered; therefore, genetic testing is not yet available. Only few cases had abnormal chromosomal analysis [6]. Our case also had normal chromosomal analysis like majority of patients with congenital arhinia.The clinical consequences of congenital arhinia are severe airway obstruction and inability to feed. The nursing care for children is especially important because the infant can’t eat and breathe at the same time without the normal nose function which will result in respiratory distress. A surgically created nasal airway or a tracheostomy tube is an important part of early management. The surgical correction of nasal airway during the neonatal period has been advocated to reduce the potential of dependency on mouth breathing or tracheostomy. Feeding difficulties secondary to impaired simultaneous sucking and breathing may be overcome by placement of an orogastric tube or a gastrostomy tube [1-6]. The reconstruction of arhinia is very complex and it should performed by a multidisciplinary team which includes ENT and plastic surgeons, and prosthodontists. The arhinia reconstruction includes reconstruction of the nasal cavity and reconstruction of the external nose. Most authors agree that reconstruction can be delayed at least until preschool years when facial development is nearly completed Source of Support: NilConflict of Interest: None


Areca nut, commonly called as betel nut or supari, is a fruit of areca catechu palm tree, which is native of South Asia and Pacific Islands. The seed or endosperm is consumed fresh, boiled or after sun drying or curing. Chewing areca nut is thought to have central nervous system stimulating effect and along with this it is known to have salivary stimulating and digestive properties. According to the traditional Ayurvedic medicine, chewing areca nut and betel leaf is a good remedy against halitosis. It is also used for its deworming property. Along with these beneficial effects of areca nut one of its most harmful effects on the human body in general and oral cavity in particular is the development of potentially malignant disorder called Oral Submucous Fibrosis.The present paper discusses in detail the effects of the components of areca nut on pathogenesis of Oral Submucous Fibrosis. Key words:Areca nut, oral submucous fibrosis, potentially malignant disorder, supari. Areca nut or supariis a fruit of areca catechu palm tree, which is native of South Asia and Pacific Islands. It is commonly called as betel nut as it is often chewed wrapped in betel leaves.While fresh, the husk is green in color and the nut inside is very soft whereas in a ripe fruit the husk becomes yellow or orange and the fruit inside hardens to a wood like consistency . The seeIndian culture and tradition hold areca nut and betel leaves in high esteem. Considered an auspicious ingredient in Hinduism, the areca nut is still used along with betel leaf in religious ceremonies and also while honouring individuals in most of Southern Asia. In the Indian subcontinent the chewing of betel leaf and areca nut dates back to the pre-Vedic period of Harappan Empire. Formerly in India and Sri Lanka it was a custom of the royalty to chew Areca nut and betel leaf. There was also a custom to chew Areca nut and betel leaf among lovers because of its breath-freshening and relaxant properties .Areca nuts are chewed with betel leaf for their effects as a mild central nervous system stimulant .The effeOral submucous fibrosis (OSF) is a chronic, insidious oral mucosal condition that occurs predominantly among Indians and occasionally in other Asians especially Taiwanese and sporadically in Europeans. It was first described by Pindborg and Sirsat . It is rThe hallmark of the disease is submucosal fibrosis that affects the oral cavity and progressively involves the pharynx and the upper esophagus. It is characterized by juxta-epithelial inflammatory reaction followed by chronic change in the fibro-elasticity of the lamina propria and is associated with epithelial atrophy. This leads to burning sensation in the oral cavity, blanching, and stiffening of oral mucosa and oropharynx, resulting in restricted mouth opening which in turn causes limited food consumption, difficulty in maintaining oral health, and impairs the ability to speak ,9.The presence of palpable fibrous bands is a diagnostic criterion for OSF. The fibrous bands occur especially in the buccal mucosa,retromolar areas, and around the rimaoris. When the tongue is affected, it is devoid of papillae and becomes smooth. Its mobility, especially the protrusion, is impaired. The opening of the mouth is restricted. Some investigators adhered to the earlier signs and symptoms such as pain, history of vesicles and ulcers, and blanching of the mucosa for diagnosis of OSMF .Due to this characteristic clinical appearance there are very few conditions that need to be differentiated from it such as scleroderma, anemia and lichen scerosus.Scleroderma is an autoimmune condition affecting the connective tissue characterized by intense fibrosis of the skin with internal organ involement. Although there is restricted mouth opening, microstomia and xerostomia in these patients, presence of Raynaud’s phenomenon, widening of the periodontal ligament space and osseusresorbtion of the mandible, increased collagen fibers in the deep layers of the dermis and serological tests helps us to differentiate it from OSF . UsuallyAlthough the pathogenesis of the disease is thought to be multifactorial, chewing of betel quid/areca nut has been recognized as one of the most significant risk factors for OSF .The tremendous rise in the incidence of this condition has been reported. Worldwide estimates in 1996 indicate that 2.5 million people were found to be affected by this disease, whereas in 2002, in the Indian continent alone, the statistics for OSF was about 5 million people (0.5% of the population of India) ,15.In recent years marked increase in the occurrence of OSF was observed in many parts of India like Bihar, MP, Gujarat and Maharashtra and the younger generation are suffering more due to incoming of areca nut products in different multicolored attractive pouches .The prevelance of OSF among patients attending dental OPD in Jaipur, Rajasthan, India in 2012 was found to be 3.39% .Therefore OSF is considered as a public health issue in many parts of world including the UK, South Africa, and many Southeast Asian countries ,15. The The malignant transformation rate of OSF has been reported to be around 7.6% over a 17-year period .The initial pathology of OSF is characterized by juxta-epithelial inflammation, including edema, large fibroblasts and an inflammatory infiltrate, consisting primarily of neutrophils and eosinophils .Later, collagen bundles with early hyalinization are seen and the acute inflammatory infiltrate contains more chronic cell types,such as lymphocytes and plasma cells, occasionally resembling lichenoid mucositis. In more advanced stages, OSF is characterized by formation of thick bands of collagen and hyalinization extending into the submucosal tissues and decreased vascularity. The epithelium lining frequently becomes thin and loses melanin or becomes hyperkeratotic. Occasionally dysplastic changes occur in the epithelium. Inflammation and fibrosis of minor salivary glands canalso be seen. Muscle degeneration occurs in advancedstages of OSF .A number of etiological factors have been discussed to play a role in the pathogenesis of this disease. Factors include areca nut chewing, ingestion of chillies, genetic and immunologic processes, nutritional deficiencies. Various epidemiological studies and histopathological effects on fibroblast and keratinocytes support the chewing of areca nut as one of the most important risk factors for OSF .Areca nut is made up of alkaloid and flavonoid components. Four alkaloids namely arecoline, arecaidine, guvacine, and guvacoline have been identified in areca nut, of which arecoline is the most potent agent and plays a major role in the pathogenesis of OSF by causing an abnormal increase in collagen production. The flavonoid components like tannins and catechinshave been found to have some direct influence on collagen metabolism .Basic mechanisms involved in the pathogenesis of OSF can be divided into four steps:1. Occurrence of the chronic inflammation at the site of betel quid placement2. Increased collagen synthesis3. Collagen cross-linking4. Decreased collagen degradation- Occurrence of the chronic inflammation at the site of betel quid placement:The areca nut chewing habit varies among individuals. The most common habit is placement of the betel quid in the vestibule for varying duration and frequency. Due to the constant contact between the betel quid and the oral mucosa, the alkaloids and the flavonoidsfrom the quid are absorbed and undergoes metabolism. These constituents along with their metabolites serve as a constant source of irritation to the oral mucosa. Along with this chemical irritation, the mechanical irritation of the oral mucosa also occurs due to the presence of the coarse fibers in the betel quid. The microtrauma resulting from this continues friction of coarse fibers of areca nut facilitates the diffusion of betel quid alkaloids and flavonoids into the subepithelial connective tissue, resulting in juxtaepithelial inflammatory cell infiltration . Due to Cytokines like interleukin 6 (IL 6), tumor necrosis factor (TNF), interferon α and growth factors like Transforming growth factor – beta (TGF-β) are synthesized at the site of inflammation . Initial-Increased collagen synthesis.TGF- β is a key regulator of Extra- cellular matrix (ECM) assembly and remodelling. It helps in activation of procollagen genes and elevation of pro-collagen proteinase levels .Procollagen genes are transcribed and translated to form pro-collagen monomeric chains (procollagen precursor). Three of these monomers assemble into a trimer triple helix which is aided by disulphide bridge formation. These trimericprocollagen chains are acted upon by N and C – terminal proteases to cleave the terminal domains and form the fibrils. The newly formed fibrils are then covalently stabilized through cross-linking to form a stable mature structure of collagen .The genes COL1A2, COL3A1, COL6A1, COL6A3, and COL7A1 have been identified as definite TGF- β targets. The transcriptional activation of types I and type VII collagen gene expression by TGF- β has been demonstrated . Due to Procollagen proteinases (PNP and PCP) helps in processing of procollagen precursors into collagen fibrils, which are soluble. Thus TGF- β modulates both processes i.e. increased procollagen gene expression and processing into fibrils by increased levels and activities of PCP and PNP .The end result is increased collagen synthesis.- Collagen cross-linkin:The lysyl oxidase (LOX) is an essential enzyme for final processing of collagen fibers into a stabilized covalently cross-linked mature fibrillar form that is resistant to proteolysis. The activity of LOX leads to the formation of insoluble collagen due to cross-linking. This gives tensile strength and mechanical properties to the fibers and thus makes them resistant to proteolysis.The LOX is a copper dependent enzyme . The conHigh levels of copper have been demonstrated in areca nut. Chewing areca nut for 5 – 30 minutes increases the soluble copper levels in the oral fluids which in turn stimulates fibrogenesis through up-regulation of LOX activity ,30.Flavonoids present in the areca nut also play an important role in the process of enhancing the cross-linking of the fibers. It has been demonstrated in in-vitro studies that presence of catechin raises the LOX activity ,32.TGF-β has been considered as an important factor in regulating the expression of LOX. The probable mechanism for this could be elevation of BMP1 by TGF-β which further mediates the bio-synthetic processing of LOX  Fig. 3)3).Thus increased LOX activity due to increased BMP and Copper levels and presence of flavonoids in areca nut leads to increased cross-linking of the collagen fibers, that are resistant to proteolysis.- Decreased Degradation of collagen:TGF-β decreases the collagen degradation by activation of tissue inhibitor of matrix metalloproteinase gene (TIMPs) and plasminogen activator inhibitor (PAI) gene.Matrix metalloproteinases (MMPs) comprise of a set of structurally related degrading proteases. Their main function is tissue remodelling by degradation of ECM in health and disease. There are many types of MMPs but few MMPs like MMP 1, MMP8, MMP13 are referred as collagenases. The activities of MMPs are regulated at the level of transcription, activation of the pro-MMPs, and inhibition of endogenous inhibitors under normal physiological conditions .TIMPs are specific inhibitors of MMPs and thus control their local activities in tissues. Studies have demonstrated increased expression of TIMPs in OSF which are responsible for inhibition of collagenase and decrease in collagen degradation ,35.TGF-β activatesTIMP gene thus decreases the collagen degradation by inhibition of the activated collagenases. The flavonoids also have been shown to inhibit the collagenase activity  Fig. 4)4).The plasminogen (Plg) activation system is an extra-cellular proteolytic system that plays an important role in tissue remodelling . PlasminPlasmin plays an important role in the activation of pro-MMPs to active form, and thus facilitates the collagen degradation. In OSF, it has been found that there is increase in PAI1 which leads to inhibition of Plg activation process  Fig. 4)4)TGF-β has been shown to play a very important role in regulation of PAI1 with its stimulatory effect .Thus there is inhibition of existing collagenase and decreased generation of active collagenase collectively resulting in decrease in collagen degradation.Apart from activation of TIMPs and PAI genes, another process which is responsible for decreased degradation of collagen is inhibition of collagen phagocytosis. Collagen degradation by fibroblast phagocytosis has animpor-tant role in physiologic collagen turnover. In vitro culture studies have demonstrated that there is reduction in the collagen phagocytic cells in OSF fibroblasts which was thought to be dose dependent with the amount of arecoline/arecaidine ,40.The alkaloid and flavonoid content of the areca nut plays a very important role in the major events that occur in pathogenesis of OSF. They enhance the collagen production, strengthen the cross-linking and reduce their degradation by various discussed molecular pathways. It is a progressive process and hence relieving the patient’s symptoms to improve the life quality forms the basis of its management. Its potential to turn into malignancy is also of concern. It is well said that ‘Prevention is better than cure’ and it holds true in case of the management of this irreversible disease. Thus cessation of the areca nut chewing habit forms the mainstay for the therapy.


The Student Council (SC), part of the International Society for Computational Biology (ISCB), aims at nurturing and assisting the next generation of computational biologists. Our membership and leadership are composed of volunteer students and post-docs in computational biology and related fields. The main goal of our organisation is to offer networking and soft skill development opportunities to our members.The Student Council Symposium (SCS) takes place every year, directly preceding the ISMB/ECCB conferences. SCS 2014 marked the tenth consecutive edition of the event, after the success of previous years' editions .The Student Council Symposium is a one-day event. Following the success of previous years, SCS 2014 kicked off with a scientific speed dating session. During this session our delegates have to find a partner to introduce themselves to, and they discuss their scientific backgrounds and interests. After five minutes they must switch partners, and this goes on until the allotted time runs out. The traditional scientific component of the meeting consisted of two keynote presentations by senior researchers, twelve oral presentations by delegates, and a poster session.th edition of the Student Council Symposium, Dr. Manuel Corpas, Dr. Jeroen DeRidder, Dr. Nils Gehlenborg and Dr. Geoff Macintyre, former members of the Student Council, delivered a welcome address and an overview of the Student Council's history.To celebrate the 10Dr. David Bartel  and Dr. Ashlee Earl  generously agreed to deliver the keynote addresses at SCS 2014. In addition, Abhishek Pratap, Senior Research Scientist in Bioinformatics at our institutional partner Sage Bionetworks, gave a short presentation about Enabling Collaborative and Reproducible Research through the Synapse software.http://scs2014.iscbsc.org/booklet-2014.SCS 2014 received 76 submissions from students, which were peer-reviewed by 23 independent reviewers. More than 50 abstracts were accepted for poster presentations, and 12 abstracts were invited to deliver an oral presentation. Extended abstracts of oral presentations are included in this report. All abstracts are available online in the SCS 2014 booklet The commemorative welcome address opened the day, and Drs. Corpas, DeRidder, Gehlenborg and Macintyre provided our delegates with their points of view on the evolution of the Student Council during its first 10 years. Having now become young group leaders and senior postdocs, they offered an interesting perspective on the impact the Student Council has had on the development of their carreers.Dr. David Bartel's keynote followed the welcome address. In his talk, Dr. Bartel gave an overview of the current understanding of microRNAs, the progress in predicting their targets, and how measurements of their regulatory effects have revealed an unexpected developmental switch in the nature of mRNA translational control.Dr. Ashlee Earl gave us an overview of her work on tackling longstanding and emerging challenges in infectious disease by taking advantage of new sequencing technologies. In particular, she described her group's work on tackling the emergence of multi-drug resistant strains of pathogens through the development of approaches and tools to examine the drug resistant Mycobacterium tuberculosis.The first oral presentation was delivered by Yassine Soulimi, who introduced the COSMOS software for cloud enabled next generation sequencing analysis . COSMOS When performing multiple sequence alignments, most users tend to rely on the default parameters of the algorithm. A different parameter setting may however have great impact on the quality of the output alignment. Parameter advising is the task of selecting good parameters for a given set of input sequences to be aligned. Dan DeBlasio presented his work on constructing improved advisors for multiple sequence alignment .Lin-Yang Cheng described his efforts to enhance quantitative protein-level conclusions in experiments with data-independent spectral acquisition by the statistical elimination of spectral features with large between-run variation. His results show that his approach achieves an accuracy that exceeds the standard approach of using three spectral features with the highest intensity between runs .Microsatellites are short, tandem-repeated DNA sequences which make up approximately 3% of the human genome. The expansion of these microsatellite repeats has been linked to many neurological and developmental disorders. Harriet Dashnow presented her work on developing a microsatellite genotyping algorithm that addresses several issues regarding the length determination of microsatellites from next-generation sequencing data, and provides a highly accurate and more detailed analysis of microsatellite loci .Yi Zhong reported the development of novel computational tools to gain biological insight from Ribo-seq and RNA-seq data in a fast and accurate way. By using transcriptome-scale ribosome footprinting data from leukemia cell lines, he identified drug-sensitive genes showing both decrease of translational efficiency and accumulation of ribosome occupancy at 5'UTRs. These genes constitute potential therapeutic targets for cancer .The usage of tetranucleotides for genomes analysis is a promising approach for the evaluation of host-parasite coevolution and gene exchange within the mycobacteriophage population. Benjamin Siranosian talked about computationally inexpensive methods, based on the usage of tetranucleotides, that are also independent of gene annotation, and their usefulness for phage clustering and the analysis of evolutionary relationships .Haeewook Lee presented his work on the detection of structural variants involving insertion sequence elements in mutation accumulation lines of Escherichia coli. By extending an A-Bruijn graph based structural variant detection framework he was able to tackle the challenge of obtaining direct estimates on insertion, deletion and recombination event rates.Using a Random Forest machine learning approach, Russel Sutherland reported results on the discrimination between cancer differentiation subtypes. By applying the algorithm to exome sequencing data from tumour and normal tissue samples from 1798 patients, they were able to discriminate between 5 cancer types with high accuracy.Alex Salazar presented Emu, an algorithm that resolves alternate representations of larger sequence variants (LSVs) by comparing variants across genomes. Emu improves the analysis of LSVs in bacterial genomes by reducing cross-sample noise resulting from per-sample variant calls .Vikas Pejaver presented MutPred2, a method for the prediction of pathogenicity of missense variants and their molecular effects. The software can be used to guide downstream experiments for elucidating the molecular basis of disease, and to assist in the development of therapeutic strategies.Y. pestis. The resulting benchmark dataset can be highly useful for the analysis of protein interaction networks functioning within an important human pathogen [Sarah Keasey presented her work on systematically identifying and analysing thousands of direct binary protein interactions within pathogen .On behalf of Amin Ardeshirdavani, Prof. Yves Moreau presented NGS-Logistics, a platform to analyse NGS data in a distributed way, while guaranteeing privacy and security . The fraThanks to the generous contribution of the Swiss Institute of Bioinformatics, two travel fellowships were awarded to Sarah Keasey and Vikas Pejaver to attend SCS 2014.Based on the votes of the SCS delegates, a judging committee awarded three speakers with one best oral and two best poster presentations awards. The best oral presentation award went to Harriet Dashnow for her work entitled "Genotyping Microsatellites in Next-Generation Sequencing Data". The first place in the best poster presentation awards went to Alex Salazar for his work, "Investigating large sequence variants in drug resistant Mycobacterium tuberculosis". The second place in the poster presentation awards went to Sarah Keasey for her work, "The Road To Linking Genomics And Proteomics Of Pathogenic Bacteria: From Binary Protein Complexes To Interaction Pathways".In addition to the aforementioned awards, Russell Sutherland and Dilmi Perera received F1000 awards for their poster presentations at SCS 2014.This year's number of submissions and participants saw a slight decline in comparison with the previous edition. Visa issues and the general lack of funding seem to be the main reasons according to our surveys. All these issues notwithstanding, the quality of the keynote presentations, the 12 oral presentations and the poster session once again made the Student Council Symposium a great success.th edition of SCS to be held in Dublin, Ireland, preceding ISMB/ECCB 2015. For further information regarding the Student Council, its events, internships and community, please visit http://www.iscbsc.org.Preparations are already ongoing for the 11


Culicoides spp.), and the technique has proven its suitability to accurately identify field-collected biting midges on a large scale. We have extended our insect vector reference database to also include culicid mosquito and phlebotomine species. Currently, biomarker mass sets are determined for the imagos of 15 phlebotomines , as well as for both imagos and larvae of 38 Central European culicid species, including all established and presumptive Aedine invasive species such as the Asian tiger mosquito Aedes albopictus or the Asian bush mosquito Ae. japonicus. In addition, biomarker mass sets of eggs were determined for indigenous and invasive container-inhabiting Aedine mosquitoes  allowing to identify eggs collected in oviposition traps in the framework of surveillance programs. Eggs can be identified by MALDI-TOF MS either singly or in pools  for those species of which at least 3 eggs are present in the sample. We are continuously expanding our database, e.g. to also include the remaining mosquito species whose eggs can be encountered in surveillance programs of container-inhabiting mosquitoes in Europe, i.e. species usually breeding in tree holes or rock pools in southern Europe . Taken together, protein profiling by MALDI-TOF MS is a quick and inexpensive tool to accurately identify adult and immature stages of insect vectors collected in the field, and the technique has the potential to become the method of choice for a centralized, robust and high throughput screening of insect vector populations in connection with surveillance programs. The simple sample preparation can be done in peripheral laboratories and the slides be sent to the measuring laboratory. The future application of the method will include the accomplishment of the measurement with a mass spectrometry device anywhere and the identification via our online platform.Identification of insect vectors is primarily carried out using morphological features, which can be a time-consuming and difficult task. PCR-based approaches have been developed for the identification of a number of vector species. We have recently established matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), which has come of age for the high throughput identification of microorganisms, to identify imagos and larvae of biting midges (


Inflammatory myofibroblastic tumor (IMT) is a benign pseudoneoplastic inflammatory condition with the potential for persistent local growth and recurrence that rarely affects the orbit. We report a very rare case of anterior orbital IMT in a child who presented with gradually progressive mass in left eye for 16 months. Ocular examination showed a cauliflower like exophytic mass at 360 degrees of the perilimbal area covering the entire cornea and obscuring the visualization of anterior and posterior segments. The right eye was phthisical. CT scan showed a lobulated exophytic soft tissue mass in the preseptal region and along the anterior portion of the left globe extending from medial canthus to the lateral canthus. Enucleation of the left eye was performed and the histopathological examination confirmed the diagnosis of IMT. This report aims to raise awareness about this rare ocular entity and emphasizes its early treatment as delay can result in loss of the eye. Inflammatory myofibroblastic tumor (IMT) is a benign pseudoneoplastic inflammatory condition of unknown etiology and diverse morphology, also referred to as pseudosarcomatous myofibroblastic proliferation, xanthomatous pseudotumor, and plasma-cell granuloma .IMT was originally described in lungs and other sites such as abdomen (mesentery), retroperitoneum, and genitourinary tract. Ocular involvement has rarely been reported . It has We are reporting this case because of its rare presentation involving the eyes and the challenges involved in diagnosis.An eighteen-month-old boy was brought with the complaint of a gradually progressive painless mass in the left eye since 16 months. According to the parents, the child was unable to see with both the eyes since birth. General and systemic examination of the child was normal. Ocular examination revealed phthisical right eye  and a ca2 in preseptal region extending from lateral canthus to medial canthus of the left eye abutting the anterior globe and lacrimal gland with loss of intervening fat plane , and calponin [The basic components of IMT are lymphocytes, plasma cells, histiocytes, fibroblasts, and myofibroblasts which are present in variable proportions. Four basic histologic patterns  consist calponin .IMTs are often characterized by anaplastic lymphoma tyrosine kinase-1 (ALK1) gene rearrangements . This isAt one-year follow-up, there was no recurrence of tumor seen in our patient. However, in the case of the ten-year-old , there wOrbital IMT is a very rare entity which can present as an anterior segment mass even in early infancy. CT scan and MRI play crucial role in defining the extent of the tumor and deciding the treatment option while histopathological examination is important for confirming the diagnosis. Early diagnosis and treatment of orbital IMT are of paramount importance as delay can result in loss of the eye.


Haloferax volcanii. At least two different proteases are needed in this archaeon to accomplish the posttranslational modifications of the S-layer glycoprotein. The rhomboid protease RhoII is involved in the N-glycosylation of the S-layer protein with a sulfoquinovose-containing oligosaccharide while archaeosortase ArtA mediates the proteolytic processing coupled-lipid modification of this glycoprotein facilitating its attachment to the archaeal cell surface. Interestingly, two different signal peptidase I homologs exist in H. volcanii, Sec11a and Sec11b, which likely play distinct physiological roles. Type IV prepilin peptidase PibD processes flagellin/pilin precursors, being essential for the biogenesis and function of the archaellum and other cell surface structures in H. volcanii.The function of membrane proteases range from general house-keeping to regulation of cellular processes. Although the biological role of these enzymes in archaea is poorly understood, some of them are implicated in the biogenesis of the archaeal cell envelope and surface structures. The membrane-bound ATP-dependent Lon protease is essential for cell viability and affects membrane carotenoid content in  Membrane-associated proteases participate in a variety of processes essential for cell physiology including membrane protein quality control, processing of exported and/or membrane-anchored polypeptides, regulatory circuits, cell-signaling, the stress response and assembly of cell surface structures . Their tIntegral membrane proteases comprise two distinct groups. The first group is represented by peptidases anchored to the cytoplasmic membrane that exert their catalytic activity in an aqueous compartment  either at the aqueous-membrane boundary or after the substrate has been released or extracted from the membrane. Within this category are signal peptidases (SP), site 1 proteases (S1P) or sheddases, signal peptide hydrolases SPPA, HtpX, sortases and the energy-dependent proteases FtsH and LonB. The second group is represented by the so-called intramembrane cleaving proteases (ICliPs) which have their active sites immersed in the hydrophobic environment of the membrane . This grArchaea, one of the three domains of life, are widespread in nature but predominate in environments with extreme values of pH, temperature, salt concentration and pressure (pressure . StudiesTable 1). This mini review describes what is known about proteases associated with the cell surface of archaeal cells on the basis of complete genome sequences and biochemical and/or genetic studies. Emphasis will be placed on the proteolytic enzymes affecting the cell envelope and surface structures of the euryarchaeon Haloferax volcanii and other haloarchaea. H. volcanii grows in a wide range of salinity (1.5–3.5 M NaCl) and is a model organism to study archaeal biology due to a number of advantages including the simplicity of its culture conditions, availability of complete genome sequences and feasibility of its genetic manipulation.The genome sequences of archaea show that these unusual organisms encode a variety of proteolytic enzymes some of which have been characterized . Most ofin silico examination of the complete genome sequences of some representative archaea members. Some protease families are widely represented among archaeal genomes such as HtpX homologs, LonB, SP, and Site 2 proteases (S2Ps) whereas others are restricted to a limited number of organisms . Table 1 describes the membrane proteases that have been experimentally characterized from the Archaea domain. Some of them have been studied in more detail (SPI and TFPP-like SP) and at least a few of their endogenous substrates have been identified . However, most families have been examined to a limited extent or remain uncharacterized, and their biological relevance and/or targets are unknown .An overview of the repertoire of membrane proteases that occur in archaeal cells is shown in Table Methanococcus maripaludis FlaK; Thermococcus onnurineus and Archaeoglobus fulgidus LonB proteolytic domains; S2P transmembrane segments (TMSs) core from Methanococcus jannaschii; MCMJR1 peptidase from Methanoculleus marisnigri) providing valuable structure/function insights on these protease families (see Table 1 for references).The crystal structures of a number of archaeal membrane proteases have been solved  component of the cell wall . These sIn addition to the S-layer, archaea show very diverse and complex cell surface structures  and intense solar irradiation. In the haloarchaeon examined . The adeTable 1). In agreement with the genomic prediction, LonB has been immunolocalized in association with the cell membrane in the haloarchaea Natrialba magadii and H. volcanii. The recombinant protease derived from N. magadii (NmLon) showed DNA binding capacity in vitro, a feature in common with LonA proteases  which serve to protect their macromolecules from the damaging effects of UV light , type IV prepilin peptidase (TFPP)-like enzymes and signal peptide peptidase (SPP) have been characterized. A detailed description on the distribution and properties of these enzymes has been previously reported . SPIs pr. voltae  and H. vvolcanii  the cataiability . It is lSPII removes signal peptides from lipoproteins. Although there are numerous proteins in archaea that contain signal peptides with the lipobox motif, including several predicted to be secreted via the Tat pathway, homologs of bacterial SPII have not been identified in archaeal genomes . Thus, iH. volcanii the S-layer glycoprotein is the sole structure that constitutes the cell wall. This protein has been used to examine the molecular/structural adaptations of haloarchaeal proteins to high salt and has served as a model to study protein glycosylation in archaea  or archaeosortases (archaea). Exo and archaeosortases are polytopic membrane proteins with no sequence homology to bacterial sortases. However, they contain the conserved cysteine, arginine, and histidine residues found in the active site of sortases suggesting that they may perform similar functions , alterations in cell shape and the S-layer organization, impaired motility and decreased conjugation rates  immediately following the TMS of the substrate protein, it was proposed that this enzyme may facilitate the covalent attachment of target proteins  to a membrane lipid in contrast to sortases which attach proteins to the growing cell wall.Sortases are cysteine proteases from Gram-positive bacteria that “sort” proteins to the cell surface by covalently joining them to the cell wall or polymerize pilins to build pili . These eunctions . Recentlon rates . This woBacillus subtilis, a mutant strain in the rhomboid homolog YqgP displayed a slight decrease in glucose uptake and a defect in cell division leading to the formation of filamentous cells  and RhoII . A knock-out mutant of rhoII in H. volcanii displayed mild defects in motility and novobiocin sensitivity. This mutant strain was also affected in the glycosylation of the S-layer. In H. volcanii wild type cells the S-layer glycoprotein Asn732 is bound to an oligosaccharide containing at least 6 repeating units of sulfoquinovose-hexose (SQ-Hex) while in the mutant strain this residue contained only two SQ-Hex suggesting that RhoII controls (directly or indirectly) the protein glycosylation process in H. volcanii (Rhomboids are membrane serine proteases involved in regulatory intramembrane proteolysis (RIP) and are conserved in the three domains of life . The catus cells ; Mycobacibiotics . So far ubstrate . In thises Table . In halovolcanii .n-region leaving the h-region bound to the mature protein facilitating anchoring/assembly of pilin subunits onto the cell surface (Table 1). The archaellum is composed of unique proteins that are unrelated to bacterial flagellins. Archaeal preflagellins contain short signal peptides at the N-terminus which are similar to those of bacterial type IV pilins, the protein components of pili. These filamentous surface structures facilitate twitching motility in bacteria. TFPP-like proteases process the signal peptides of archaeal preflagellins. The enzymes present in M. maripaludis and Methanococcus voltae (FlaK), Sulfolobus solfataricus, and H. volcanii (PibD) are the most extensively characterized TFPPs of archaea (see references in Table 1). FlaK and PibD show some divergences including the length of the signal peptide, key amino acid residues surrounding the cleavage site as well as substrate preference  leading to the biogenesis of the cell wall and extracellular appendages , highlighting the importance of these enzymes in the adaptation and interaction of archaea with their environment.In prokaryotes the assembly and composition of cell surface structures are essential for the adjustment to the varying conditions of the environment and to interact with their surroundings . In the haloarchaeon Structural analysis of archaeal membrane proteases (Flak and GxGD proteases) have advanced the knowledge on the catalytic and molecular mechanism of intramembrane cleaving proteases. This will help to understand the mechanism of the eukaryotic homologous enzymes which are implicated in human physiology (regulation of immune response) and/or in the development of diseases (e g. Alzheimer).There are still many open questions in this field: e.g., endogenous substrates of most membrane proteases are unknown. Efforts should continue to better understand the role of membrane proteases in archaeal physiology.All authors made substantial contributions to the acquisition, analysis and interpretation of data for this review. All authors critically reviewed and edited the manuscript, and approved the final version before submission to publication. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Insects and mammals share an ancient innate immune system comprising both humoral and cellular responses. The insect immune system consists of the fat body, which secretes effector molecules into the hemolymph and several classes of hemocytes, which reside in the hemolymph and of protective border epithelia. Key features of wound- and immune responses are shared between insect and mammalian immune systems including the mode of activation by commonly shared microbial (non-self) patterns and the recognition of these patterns by dedicated receptors. It is unclear how metazoan parasites in insects, which lack these shared motifs, are recognized. Research in recent years has demonstrated that during entry into the insect host, many eukaryotic pathogens leave traces that alert potential hosts of the damage they have aﬄicted. In accordance with terminology used in the mammalian immune systems, these signals have been dubbed danger- or damage-associated signals. Damage signals are necessary byproducts generated during entering hosts either by mechanical or proteolytic damage. Here, we briefly review the current stage of knowledge on how wound closure and wound healing during mechanical damage is regulated and how damage-related signals contribute to these processes. We also discuss how sensors of proteolytic activity induce insect innate immune responses. Strikingly damage-associated signals are also released from cells that have aberrant growth, including tumor cells. These signals may induce apoptosis in the damaged cells, the recruitment of immune cells to the aberrant tissue and even activate humoral responses. Thus, this ensures the removal of aberrant cells and compensatory proliferation to replace lost tissue. Several of these pathways may have been co-opted from wound healing and developmental processes. Drosophila melanogaster has been particularly useful to map the underlying pathways. Using the fly as a model also provides insight into the relation between immunity and other aspects of the animal’s physiology and normal as well as aberrant development.Insects have served as excellent tools to study different aspects of innate immunity. Initially the focus in insect immunology was on the identification of microbially activated pathways and effector mechanisms. During recent years, the contribution of wound signals and of signals associated with the damage that occurs during the infection process has become increasingly appreciated. Despite the significant conceptual overlap between “Danger” and “Damage,” we will refer to them as “Damage-induced signals” or “damage” . The fruThe innate immune system in insects comprises two central and several peripheral tissues. The central tissues are (1) the fat body, which combines the tasks of the vertebrate liver and the adipose tissue and (2) different types of blood cells, which are collectively called hemocytes. The main function of the fat body within the immune system is to release soluble factors into the hemolymph . Some ofIn addition to their involvement during wound healing, which is discussed below, insect hemocytes have several functions ; (1) theBoth encapsulation and nodule formation lead ultimately to melanization due to the activity of the enzyme phenoloxidase. The zymogen prophenoloxidase is released from specialized hemocytes and activated in the hemolymph via a proteolytic cascade .Drosophila hemocytes include three cell types (ll types : (1) plall types , 2007 anll types  indicatill types , possiblPeripheral tissues comprising for example the tracheae, the epidermis, the gonads and the gut epithelium rely on the more locally restricted release of effectors such as prophenoloxidase and antimicrobial peptides and on the production of reactive oxygen species to varying extent. The induction of immune reactions in these tissues depends primarily on the imd pathway .Tenebrio mollitor, the blood-sucking bug Rhodnius prolixus and the wax-moth Galleria mellonella .Wound healing in g larvae . The scag larvae . Re-epitg larvae . The impwounding . Formatiwounding . Under sex vivo from a comprehensive array of insects, the histological appearance and the types of cells involved showed a great deal of variability for example in some species, cells appeared to lyze during the process leading to their separate classification as coagulocytes while at the other extreme blood cells appeared dispensable for clotting in some other species . Either downstream cleavage of proteases or direct recognition by surface molecules on immune tissues triggers the immune response. Nevertheless parallel to the microbially activated branch of the Toll path, a second activation path was discovered, which fitted well with the notion that the invasive activity of the microbial intruder directly activates immunity: persephone, one of the amplification enzymes in the Toll pathway was shown to be a direct substrate for a fungal proteases (PR1) that is essential for breaching the cuticular barrier  and its ligand Pvf1. Damage in this case appears to be signaled by exposure of Pvr at the wound edges which attracts Pvf1 and activation of the formation of the cellular processes that close the wounds . The loss of collagen from the wound site is most likely due to the activity of metalloproteinases, which are known virulence factors for entomopathogenic nematodes , which also acts as a detector for a proteolytic activity that is indispensable for host invasion  and its receptor (Wengen), which may act again as a damage receptor as well as Hedgehog signaling (One of the key concepts resulting from the early studies on elopment . Co-optielopment . In larvelopment . The redignaling , 2011. Aignaling .Galleria and Drosophila have become amenable to genetic analysis. RacGTPase activity could be shown to be required for formation of a syncytium from the cells adjacent to the wound site and Hippo signaling via the effector Yorkie for the same process and for polyploidization of cells near the wound site (Finally the histological changes that have been observed after wounding und site .Ras and reduced expression of genes that define cell polarity (Tumor mutants were among the earliest fly mutants identified in nature (surveyed in polarity . Inductipolarity . In addipolarity . Similarpolarity . The TNFpolarity . Therefopolarity . It appepolarity .Even sole expression of active Ras has been found to lead to cellular dysplasia . In the Drosophila wounds, hemocytes have been found to express apoptotic markers followed by induction of necrosis (Drosophila crystal cells rupture within minutes after bleeding releasing the components of the PAS (Of course not all tumors and not all stages of cancer progression are regarded as wounds. It has been debated which markers distinguish an immunogenic from a non-immunogenic form of tumor . Tumor-anecrosis . The fulnecrosis . In fly necrosis . Therefonecrosis . In addi the PAS . This is the PAS  since crDrosophila hemocytes is the above-mentioned calcineurin (One damage-associated signal that activates phagocytosis in cineurin . Interescineurin .Drosophila the mite protease Der p 1 cleaves the surface receptor PGRP-LC leading to activation of the imd pathway, providing yet another example for the key role of damage signals in insect immunity (Despite their bad reputation allergies can also be regarded as deregulated responses against noxious environmental substances such as venoms, xenobiotics, irritants and haematophagous fluids  many of immunity . PGRP-LCimmunity , one of immunity . It may immunity . The regFigures 1 and 2, Badrul Arefin drew Figure 3. All authors discussed the content of the manuscript.Ulrich Theopold wrote the initial draft of the manuscript, all authors contributed to the manuscript. Robert Krautz designed and drew The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Convex endobronchial ultrasound (C-EBUS)–guided transbronchial needle aspiration (TBNA) is an effective tool for the diagnosis of hilar, mediastinal, and central parenchymal lung lesions. However, it has a limited utility for pleural-based masses. We report a unique case of a pleural synovial sarcoma recurrence that was diagnosed by C-EBUS.The patient had a history of inguinal synovial sarcoma. He presented with cough and chest pain. Imaging of chest revealed large right pleural mass. Bronchoscopy with EBUS-TBNA diagnosed pleural recurrence of synovial sarcoma. He underwent radical resection and pathological examination confirmed the diagnosis of pleural synovial sarcoma. He experienced complete recovery and resolution of symptoms.Synovial sarcoma should be included in the differential diagnosis of pleural masses. Convex EBUS-guided biopsies can provide adequate diagnosis of large pleural tumors adjacent to the central airways without need for more invasive diagnostic procedures. Ethics committee or institutional review board approval was not obtained. It was not necessary for the case report. Informed consent was obtained from the patient.A 50-year-old man with history of inguinal synovial sarcoma resected 3 years prior presented for right-sided chest pain and a persistent cough of 3 months duration. Chest x-ray showed an almost complete whiteout of the right lung. CT scan of the chest showed a very large, multilobed, pleural-based tumor collapsing most of the right lung as well as small mediastinal and hilar lymphadenopathy Fig. . He unde1 Approximately, 11,000 cases are diagnosed in the United States every year. There are over 100 different histologic subtypes; synovial sarcomas are one of the more common ones. The most frequent sites of initial involvement include lower extremities, head and neck, trunk, upper extremities, mediastinum, and abdomen. These tumors have a high risk of metastases and a high frequency of recurrence.Fibrosarcomas are soft tissue tumors of fibroblastic origin. Once considered to be the most frequent type of sarcomas, they have since then been found to be exceedingly rare and constitute only about 1% of all soft tissue sarcomas.2 The most frequent site of metastasis was by far the lung parenchyma, followed by local recurrence, then bones and lymph nodes. Other smaller series reported similar findings.3 The pleural space has not been reported as a site of metastasis of these tumors. This is the first unique feature of this case. Secondly, and perhaps more interestingly, an adequate diagnosis was made by endobronchial ultrasound. EBUS-TBNA has emerged in the past few years as an effective tool to diagnose and stage a large number of chest malignancies. It allows sampling of mediastinal, hilar, and proximal endobronchial masses,5 but its utility for reaching pleural lesions is limited. This is mainly due to the thickness of the scope which usually limits its ability to enter the subsegmental airways. There have been multiple reports of diagnosis and staging of pleural malignancies with EBUS; however, this was possible only indirectly, through transbronchial aspiration of enlarged mediastinal lymph nodes and not the pleural mass itself.7 Only 1 case of endobronchial sampling and diagnosis of a pleural-based mesothelioma is reported in the literature.8 Although typically transthoracic biopsy would have been the first step in evaluation of our patient's tumor, we elected to start with flexible bronchoscopy for 2 reasons: First, the transthoracic biopsy of pleural sarcomas is known historically to be often difficult with a low yield. Second, and most importantly, we wanted to assess for endobronchial involvement given the size and near total collapse of the lung and evaluate ipsilateral and contralateral lymph nodes for staging purposes. Fortunately in our case the mass was large enough to be at proximity to the airways and was visualized by EBUS. The samples obtained allowed an adequate diagnosis of the histology of the mass and helped guide the next steps of management without the need for more invasive procedures.Several large series have been published looking at sites of recurrence. The largest one comes from the National Cancer institute in 1985.9 Other authors have discussed that it complements and may one day replace the use of blind transbronchial biopsies.10 Our case describes yet another clinical application of EBUS and adds further to the rapidly growing body of the literature supporting its utility in diagnosing both malignant and nonmalignant diseases of the chest.11 Traversing the visceral pleura transbronchially appears to be safe but certainly careful postprocedural monitoring of these patients is warranted because of the added risk of iatrogenic complications.In a recent review article from Great Britain, José et al concluded that since the advent of EBUS, fewer patients needed to undergo mediastinoscopies for diagnosis and staging of lung cancer.Synovial sarcoma should be included in the differential diagnosis of pleural masses. Convex EBUS-guided biopsies can provide adequate diagnosis of large pleural tumors abutting proximal airways without need for more invasive diagnostic procedures.