Then, orthotopic and metastatic breast tumours were precisely removed under the guidance of our system. The post-operative survival rate of mice was improved by 50% with the new method. Hematoxylin and eosin staining and immunohistochemical staining for MMP2 and CD11b further confirmed the precision of tumour dissection. Our method facilitated the accurate detection and complete removal of breast cancer tumours and provided a method for defining the molecular classification of breast cancer during surgery, thereby improving prognoses and survival rates.Advanced medical imaging technology has allowed the use of fluorescence molecular imaging-guided breast cancer surgery (FMI-guided BCS) to specifically label tumour cells and to precisely distinguish tumour margins from normal tissues intra-operatively, a major challenge in the medical field. Here, we developed a surgical navigation system for real-time FMI-guided BCS. Tumours derived from highly metastatic 4T1-luc breast cancer cells, which exhibit high expression of matrix metalloproteinase (MMP) and human epidermal growth factor receptor 2 (HER2), were established in nude mice; these mice were injected with smart MMP-targeting and “always-on” HER2-targeting near-infrared (NIR) fluorescent probes. The fluorescence signal was imaged to assess  According to a report by the National Cancer Institute (NCI), breast cancer is the third most frequently diagnosed cancer, with an estimated 1.38 million new cases per year56710in vivo and has been shown to be advantageous for the intra-operative, accurate localisation of tumour margins and the precise resection of lesions24Existing medical imaging technology has played an important role in pre-operative diagnosis and post-operative assessment. However, few current medical imaging methods, such as radiography, computed tomography, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography, have been designed for intra-operative use by surgeons due to the limitations of machine size or radiation in application of intra-operative image-guided surgery131819202122Tumour margin detection is dependent on precise prognosis of irregular orthotopic tumours and metastases during surgeryTo evaluate the function and efficacy of our FMI-guided BCS technique for the precise detection and complete resection of breast metastatic tumours, we used a smart fluorescent probe, MMPSense 750 FAST  to target MMP based on the following three reasons: (1) the probe can efficiently and abundantly accumulate at tumour sites due to the enhanced permeability and retention effect (EPR); (2) MMP-750 is a MMP-activatable imaging agent that is optically silent upon injection and produces a fluorescent signal after cleavage by MMP enzyme ; and (3) near-infrared (NIR) fluorescence, emitted at 750 nm, eliminates autofluorescence from the body, which can increase the accuracy of imaging data collected from biomedical applications. Additionally, NIR is undetectable by human eyes, but visible on the display monitor, facilitating simple operation procedures and minimising the learning curve.Distinguishing the subtype of breast cancer intra-operatively could provide immediate information to the surgeon and oncologist regarding further optimal therapeutic options. Therefore, the breast cancer-specific receptor human epidermal growth factor receptor 2 (HER2) was chosen as another targeting site for determining the molecular classification of breast cancer. Herein, an always-on probe, HER2Sense 645 , was used to positively and specifically target HER2.The 4T1 breast orthotopic and metastatic tumour model was used as a target model system. We found that the probes could abundantly accumulate in the tumour due to the EPR or positive targeting effects of the different probes, and the probes would stably reside in the tumour for a long time. This allowed localisation of the whole breast tumour for pre- and intra-operative visualisation with FMI and the discrimination between malignant and normal tissue types. Moreover, immediate recognition of the subtype of breast cancer could be achieved intra-operatively, and excised tissues could be further analysed post-operatively using FMI to confirm clear margins. Compared to traditional surgical methods, FMI-BCS could be used to precisely visualise and resect orthotopic and metastatic breast tumours. With regulatory approval of these imaging agents, we envision that this robust method could provide an alternative opportunity to improve the detection of the tumour margins and distinguish breast tumours with different molecular classifications in the near future.In order to determine the feasibility of tumour targeting and the optimal targeting time for precise surgery, mice were administered the MMP-750 probe via tail vein injection for dynamic imaging of the probe. As shown in in situ and further facilitate tumour resection. For early-stage detection of breast cancer (5 days after orthotopic implantation of 4T1-luc breast tumour cells), mice injected with the smart MMP-750 probe underwent FMI-guided surgery, and a separate group of mice underwent traditional surgery. As shown in in situ.We next examined whether FMI could delineate clear margins of orthotopic breast tumours Based on the biodistribution results, we chose a time point of 24 h after intravenous injection of the smart probe to perform the surgery using FMI-guided BCS. For mice injected with the MMP-750 probe, surgeons carried out the resection of the orthotopic tumour using our FMI-guided BCS navigation system . During However, for mice undergoing traditional surgery without MMP-750 injection, orthotopic breast tumours were dissected according to the surgeons’ experience and perception. Bioluminescence evaluation was carried out to determine whether the tumour was precisely resected, as shown in Given that accurately distinguishing the breast cancer subtype intra-operatively could provide immediate information to the surgeon and oncologist regarding further optimal chemotherapeutic options, we used the “always-on” HER2-645 probe, which can specifically target HER2, to detect the subtype of the breast cancer, as shown in In the clinic, precise location of the margins of metastatic tumours during surgery greatly influences patient prognosis. Herein, we used a metastatic breast cancer model to further evaluate the function and efficacy of FMI-guided BCS system . About 2To examine whether the orthotopic and metastatic tumours were completely removed, major organs of the mice were post-operatively dissected, and their fluorescence signals were quantitatively analysed. As shown in in vivo, tumour nodules dissected during surgery were analysed with haematoxylin & eosin (H&E) and immunofluorescence staining for MMP2, CD11b (the marker for tumour-associated macrophages), and HER2. As shown in To further evaluate the detection of tumour margins Finally, to assess whether FMI-guided surgery could improve the survival of mice, we compared the survival rates of mice (n = 6 in each group) undergoing FMI-guided BCS to that of mice undergoing traditional surgery. As shown in The development of more precise medical diagnosis and treatment concepts has revolutionised the treatment of breast cancer. NIR FMI-guided BCS has the potential to improve patient management by visualising breast tumour margins in real time, thereby increasing the completeness of surgery and decreasing the morbidity associated with damage to normal structures. Intra-operative imaging requires a synchronous interplay among contrast agents, tumour biology, imaging systems, and image-analysis algorithms.In this study, our surgical navigation system was updated to enhance convenience for clinical use. For example, imaging fusion algorithms were improved for real-time image registrationMMPs play an important role in the tumour microenvironment and affect orthotopic and metastatic tumour progression; thus, non-invasive intra-operative imaging of MMP allows for significant improvement of detection of tumours on the (sub)millimetre scale. Furthermore, imaging of the breast cancer cell surface receptor HER2 could provide additional evidence of breast tumour detection and could distinguish the breast cancer subtype for oncologists to carry out additional therapies. At present, the use of fluorescent probes is a major challenge in tumour margin detection for surgical applications. Although the fluorescent dye indocyanine green has been used in clinical practice, it does not have the ability to provide a high signal-to-background ratio due to its nonspecific targeting and “always-on” fluorescenceFor breast cancer patients with liver metastases, if the patient was found to have “primary” liver cancer before surgery, FMI-guided surgery using the HER2 probe will identify the true primary tumour in the breast during surgery and increase the precision of cancer surgery. As the next step, we intend to construct a dual-targeted (MMP and HER2) probe to further improve the sensitivity of tumour margin detectionIn summary, FMI-guided BCS could improve the detection of tumour margins and reduce the presence of residual tumour tissue after surgery, thereby improving prognoses and survival rates. FMI-guided BCS may be a powerful tool for clinical applications in the detection of human breast tumours in the futureFMI-guided surgery was performed using our surgical navigation system, as previously described2.4T1-luc cells were cultured in Roswell Park Memorial Institute (RPMI) 1640  supplemented with 10% foetal calf serum  and were maintained at 37 °C in 5% COMMP-750 and HER2-645 imaging contrast probes  were used for intra-operative imaging. According to the manufacturer’s recommendations, the probes were reconstituted with 1.2 mL of 1× phosphate-buffered saline (PBS) before intravenous injection into animals at a dose of 2 nmol (100 μL) per mouse. The remaining probes were stored at –80 °C and protected from light.6 4T1-luc cells in 1× PBS were orthotopically transplanted into the lower right mammary fat pads of 5-week-old athymic female BALB/c nude mice. Tumour growth was monitored based on palpation and bioluminescence imaging . As shown in All animals were purchased from the Department of Experimental Animals, Peking University Health Science Center. All experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at Peking University (Permit Number: 2011-0039), and all the methods were carried out in accordance with the approved guidelines. A total of 1 × 10In order to evaluate the feasibility of breast tumour detection and the biodistribution time, we randomly chose six nude mice bearing 4T1-luc tumour cells for about 5 days. After injection of the MMP-750 and HER2-645 probes separately, mice were placed in the Berthold equipment for continuous monitoring at different time points.A total of 36 mice were randomly divided into four groups as shown in Breast tumour tissues were excised during surgery and frozen at –80 °C in optimum cutting temperature (OCT) compound  immediately after surgery. The tumours were cryosectioned  to yield sections of 4-μm thickness for H&E staining and MMP2 and CD11b immunofluorescence staining. The frozen OCT sections were fixed in acetone for 10 min. Primary mouse anti-human MMP2 antibodies  were used to label the tumour environment. Secondary antibody staining was performed using donkey anti-mouse Alexa Fluor 594 antibodies . Alternatively, primary rat anti-mouse CD11b antibodies (BD Bioscience) were used to label tumour-associated macrophages in the tumour environment. Secondary antibody staining was carried out using donkey anti-rat Alexa Fluor 594 antibodies. For HER2 evaluation, primary rabbit anti-mouse HER2 antibodies (BD Bioscience) were used to label the orthotopic tumour. Secondary antibody staining was performed using donkey anti-rabbit Alexa Fluor 594 antibodies. The sections were washed twice and mounted with medium containing DAPI .t-tests were used to determine significant differences. Differences with P-values of less than 0.05 were considered statistically significant. The statistical analysis was conducted using Prism 4.0 .Data are presented as the average of three independent experiments. One-way analysis of variance (ANOVA) and Tukey’s multiple comparisons tests or Student’s How to cite this article: Chi, C. et al. Increased precision of orthotopic and metastatic breast cancer surgery guided by matrix metalloproteinase-activatable near-infrared fluorescence probes. Sci. Rep.5, 14197; doi: 10.1038/srep14197 (2015).


The paper proposes a novel nano bearing formed by the physical adsorption of the confined fluid to the solid wall. The bearing is formed between two parallel smooth solid plane walls sliding against one another, where conventional hydrodynamic lubrication theory predicted no lubricating effect. In this bearing, the stationary solid wall is divided into two subzones which respectively have different interaction strengths with the lubricating fluid. It leads to different physical adsorption and slip properties of the lubricating fluid at the stationary solid wall respectively in these two subzones. It was found that a significant load-carrying capacity of the bearing can be generated for low lubricating film thicknesses, because of the strong physical adsorption and non-continuum effects of the lubricating film. In micro/nano devices, the coupled solid surfaces are often parallel to and slide against one another2γs in the latter) ranges between −1 and 1. A higher magnitude of γs indicates a more severe interfacial slippage, and a magnitude of γs equal to unity shows the most severe interfacial slippage, which makes the boundary film on the contact surfaces halted in motion or the greatest increases the moving velocity of the boundary film on the contact surface. The boundary film interfacial slippage can thus reduce or increase the mass flow rate of the lubricating film through the contact depending on the operating condition and where the interfacial slippage occurs. It may thus be harmful or beneficial for the performance of a lubricated micro/nano contact. A strong, medium-level or weak adsorption of the confined fluid to the solid wall in a nano channel may be unavoidably present depending on the interaction strength between the confined fluid and the wall1112131411121314The reasons for the failure of conventional hydrodynamic lubrication theory to predict the performance of a lubricated micro/nano contact are that such a theory only considered homogeneous contact surface properties, neglected the factors of the physical adsorption and the slippage of the lubricating film at the contact surface, and was based on the assumption of a continuum lubricant567891112131415On the other hand, molecular dynamics simulations showed that the fluid confined in a nano channel actually exhibits non-continuum properties showing varying local densities and viscosities across the channel height111213141112131418The lubrication in a micro/nano contact may actually be the physical adsorbed layer boundary lubrication, which heavily depends on the interaction between the adsorbed layer and the contact surface. In this regime, the lubrication does not follow conventional hydrodynamic lubrication theory, and a new theory taking into account the physical adsorption, interfacial slippage and non-continuum effects of the boundary film may need to be developedContinuum hydrodynamic lubrication theory has shown that hydrodynamic lubrication can be generated between two parallel smooth solid surfaces sliding against one another, by artificially designing the contact-fluid interfacial slippage at the specific surfacesThe boundary lubrication in a nano contact was ever studied by atomistic simulations (including molecular dynamics simulation and Monte Carlo simulation), which however were usually quite time taking and computer storage consuming and were often only applicable for very small contact areas2324et al.et al.et al.A lot of continuum or quasi-continuum models have also been proposed for simulating the flow of a fluid confined in a nano channel. Hansen et al.et al.The interesting phenomena concerning the molecular spin, rotational viscosity and angular momentum of a confined fluid in a nano channel were also studied by MDS. Moore The flow factor approach model has been proposed for studying the physical adsorbed layer boundary lubrication1821The flow factor approach model as well as the molecular dynamics simulation results showed that the average velocity across the channel height of a confined fluid in a nano channel in the Couette flow is indeed equal to that calculated from conventional hydrodynamic lubrication theory, while the magnitude of the flowing velocity of this confined fluid in the Poiseuille flow is reduced because of the non-continuum effect i.e. the discontinuity and inhomogeneity effects of the confined fluid across the channel height18According to the underlying mechanisms of the load-carrying capacity generation in a nano bearing, the present paper attempts to study the performance of a novel nano slider bearing formed between two parallel smooth solid plane walls which is dependent on the physical adsorption, by using the flow factor approach model. Different from the previously studied bearing taking the homogeneous surface properties shown in ref. Based on the flow factor approach model, the present paper presents an analysis for the load-carrying capacity of the studied bearing. The condition for the formation of the bearing was obtained. The calculation results showed that significant pressures and then pronounced load-carrying capacities can be generated in the studied bearing for low lubricating film thicknesses, because of the strong physical adsorption and non-continuum effects of the lubricating film. The optimum condition for the maximum load-carrying capacity of the bearing was also obtained.1” and “a2” subzones which are respectively made of different materials or covered with different coatings. The adsorption of the fluid to the wall surface in the “a1” subzone is significantly stronger than that to the wall surface in the “a2” subzone. The confined fluid may slip or not slip at the wall surfaces in these two subzones depending on its adsorptions to these wall surfaces.The whole lubricated area of the studied bearing is divided into the “I” and “II” subzones, which respectively denote the bearing inlet and outlet zones. The Cartesian coordinate system is shown in y” coordinate direction, the confined fluid was assumed not to flow, i.e. no side leakage was assumed in the bearing. Such an assumption was also often taken in the analysis of a conventional hydrodynamic bearingy” coordinate direction is much bigger than that in the “x” coordinate direction so that the fluid side flow is negligible compared to the fluid total flow into the contact. In this case, the assumption can give a good prediction for the load-carrying capacity of the bearing. For the contact size in the “y” coordinate direction comparable to that in the “x” coordinate direction, the side leakage effect may need to be considered, and a correction factor can be introduced to modify the carried load of the bearing calculated based on the no slide leakage assumption to account for the side leakage effect as ever done in the analysis of the conventional hydrodynamic bearingIn the “In the present analysis, the frictional heating in the bearing was also neglected. This may be allowable when the sliding speed is low. However, for a high sliding speed, this assumption may be not allowable, and a thermal analysis for the bearing may be required. The present work can give a fundamental result for the studied bearing, and regarding the friction heating effect a correction factor can also be introduced to modify the present obtained results, as ever done in the conventional hydrodynamic bearing analysisThe coupled wall surfaces in the present bearing were treated as ideally smooth and rigid. These treatments can simplify the problem. For low lubricating film pressures and the protrusion on the wall surface much lower than the lubricating film thickness, these treatments are allowable. However, when the film pressure is so high that the caused wall surface elastic deformation is comparable to the film thickness, the influence of the wall surface elastic deformation on the bearing performance should be considered. On the other hand, when the wall surface protrusion is comparable to the film thickness, the wall surface roughness effect should also be considered. These could be put as interesting topics in the future research. Furthermore, since the present paper addresses the physical adsorption effect on the load-carrying capacity of the bearing, here the wedge effect between the coupled walls is neglected, i.e. the two walls of the bearing are parallel to one another. Nevertheless, the wedge effect between the walls is also important for the carried load of the bearing as has been known from conventional hydrodynamic lubrication theoryFinally, since the present paper thrusts efforts into the study on the load-carrying capacity of a nano bearing contributed by physical adsorption, the effect of the surface pressures due to the wall interactions on the carried load of the bearing is neglected, i.e. the carried load of the bearing calculated here is contributed by the lubricating film. Nevertheless, the present calculation is usually the main portion of the load-carrying capacity of the bearing and sufficient, as the surface pressure effect is usually weak and negligible when the lubricating film thickness is a bit higher than 1 nm36Based on the above mentioned assumptions, according to the flow factor approach model for the flow of the confined fluid in a nano channelh and p are respectively the film thickness and pressure of the confined fluid, x is the coordinate in the flow direction of the confined fluid shown in S is actually the ratio of the Poiseuille flow rate of the non-continuum fluid to that of an equivalent continuum fluid. h is below the critical film thickness where A conventional (continuum) hydrodynamic lubrication theory was ever used for studying the performance of a molecularly thin film lubricated contact by incorporating the surface pressures because of the wall interactions21A similar equation can be implemented for the “II” subzone and it reads:where the meanings of the respective parameters are respectively same with those in Eq. S(h) in Eqs. h, the pressure distributions in the “I” and “II” subzones can respectively be solved from these two equations by using the flow continuity condition and the pressure boundary conditions As the flow continuity requires, a1” subzone is stronger than that to the wall surface in the “a2” subzone, Because the adsorption of the confined fluid to the wall surface in the “If h. For the same, if h. As As the flow continuity requires, for a given operating condition, u is the speed of the moving solid wall, and Let u is high enough, uFor a given operating condition, if the interfacial slippage occurs, For constant It is solved from Eq. The load per unit contact length carried by the bearing is:Define the following dimensionless parameters:Here, The dimensionless maximum pressure is:The dimensionless load carried by the bearing is:For no interfacial slippage occurrence i.e. 1” subzone and the relatively high fluid-wall interfacial shear strength at the wall surface of the “a2” subzone so that the fluid slippage respectively occurs at the “a1” wall surface in the “I” subzone and at the moving wall surface in the “II” subzone. In this case, If Actually, the load-carrying mechanism of the bearing may be the combined effects of the physical adsorption, non-continuum and interfacial slippage of the confined fluid. The condition for the formation of the bearing is: Because According to Eq. (5) Optimum geometry of the bearing:ψ for the maximum load-carrying capacity of the bearing is:The optimum value of In this optimum condition, the dimensionless load carried by the bearing is:where h, increasing both the interaction strengths between the confined fluid and the “a1” and “a2” walls yields lower magnitudes of From Eq. The parameters where The parameters where The parameters where 2” subzone is relatively weak, and the interaction between the confined fluid and the wall in the “a1” subzone is respectively taken as medium-level and relatively strong. In the calculations, nm, nm for the medium-level interaction between the confined fluid and the wall in the “a1” subzone, and nm for the relatively strong interaction between the confined fluid and the wall in the “a1” subzone. The values of Exemplary calculations were made. In these calculations, the interaction between the confined fluid and the wall in the “a1” subzone is respectively relatively strong and medium-level. The value of 1” and “a2” subzones. For a given nanometer-scale film thickness h, the increase of the adsorption of the confined fluid to the wall in the “a1” subzone significantly increases the value of h for different positive values of 1” subzone is medium-level. Attend that in this figure h for different negative values of 1” subzone is medium-level. The interfacial slippage in h for 1” subzone is relatively strong. The interfacial slippage in h for different negative values of 1” subzone is relatively strong. Similar as in h and given values of 1” subzone significantly increases the value of The comparison between μm. The used lubricant is a common oil with short-chain molecules and its viscosity at ambient condition is nm. The stationary wall surface in the “I” subzone is covered with a hydrophilic coating such as the material of TiO2 so that the interaction between this wall surface and the lubricant is medium-level; The physical adsorption data of the confined lubricant in the “I” subzone are assumed as those shown in nm. In this case, for nm, the optimum value  per unit contact length carried by the bearing in this optimum condition is 21.12 N/m.For evaluating the performance of the present bearing, the results for an exemplary bearing are here given. The total width The paper proposes a novel nano bearing based on the different physical adsorptions of the lubricating film to the specific contact surfaces. The bearing is formed by two parallel smooth solid plane walls sliding against one another. Conventional hydrodynamic lubrication theory denied the formation of such a bearing.Based on the flow factor approach model, an analysis was derived for the load-carrying capacity of this bearing. The condition for the formation of this bearing was derived to be: How to cite this article: Zhang, Y. Novel nano bearings constructed by physical adsorption. Sci. Rep.5, 14539; doi: 10.1038/srep14539 (2015).


The evaluation of fluid responsiveness in patients with hemodynamic instability remains to be challenging. This investigation aimed to determine whether respiratory variation in carotid Doppler peak velocity (ΔCDPV) predicts fluid responsiveness in patients with septic shock and lung protective mechanical ventilation with a tidal volume of 6 ml/kg.We performed a prospective cohort study at an intensive care unit, studying the effect of 59 fluid challenges on 19 mechanically ventilated patients with septic shock. Pre-fluid challenge ΔCDPV and other static or dynamic measurements were obtained. Fluid challenge responders were defined as patients whose stroke volume index increased more than 15 % on transpulmonary thermodilution. The area under the receiver operating characteristic curve (AUROC) was compared for each predictive parameter.r = 0.84; p < 0.001).Fluid responsiveness rate was 51 %. The ΔCDPV had an AUROC of 0.88  0.77–0.95); followed by stroke volume variation , passive leg raising , and pulse pressure variation . The ΔCDPV was a statistically significant superior predictor when compared with the other parameters. Sensitivity, specificity, and positive and negative predictive values were also the highest for ΔCDPV, with an optimal cutoff at 14 %. There was good correlation between ΔCDPV and SVI increment after the fluid challenge (ΔCDPV can be more accurate than other methods for assessing fluid responsiveness in patients with septic shock receiving lung protective mechanical ventilation. ΔCDPV also has a high correlation with SVI increase after fluid challenge. In a patient with acute hemodynamic instability, a fluid challenge will cause an increase in stroke volume, according to the Frank-Starling curve . This inCurrently, both static and dynamic parameters are utilized for prediction of fluid responsiveness. Static parameters  are much less reliable than dynamic parameters, which are based on respirophasic variation in stroke volume  . Most coThis was a single-center, prospective, cohort study. Inclusion criteria were mechanical ventilation, septic shock, and hemodynamic instability for which the attending intensivist determined the need for fluid challenge based on signs of inadequate tissue perfusion according to Surviving Sepsis Campaign recommendations . The invBefore each fluid challenge, carotid peak systolic velocity was measured with a Micromaxx System , using a 5–10-mHz linear array transducer. After procuring a longitudinal view of the common carotid artery, pulsed Doppler analysis at 2 cm from the bifurcation was performed. The sample volume was positioned at the center of the vessel, with angulation at no more than 60°. Maximum and minimum peak systolic velocities were obtained in a single respiratory cycle  for calculating the sample size and for the statistical analysis.Continuous variables were reported as the mean (standard deviation) if they were normally distributed or the median (interquartile range) if they were not normally distributed, using the Shapiro–Wilk test. Preload indices were compared in responders and non-responders using the Mann–Whitney test. Categorical variables were expressed as the number of measurements (%) and were compared by the chi-squared test. For analyzing the trend in response at repeated fluid challenges per patient, we used the Cochran–Armitage test. We constructed receiver operating characteristic (ROC) curves for static and dynamic indices of preload to determine the ability to predict fluid responsiveness, and their area under the curve was compared using the Hanley–McNeil test . OptimalA total of 59 fluid challenges were performed in 19 patients, with a responsiveness rate of 51 %. In eight patients (40 %), the velocity-time integral at the left ventricle outflow tract was not obtained due to an unfavorable transthoracic echocardiographic window. Baseline characteristics of the patients are shown in Table p < 0.001; 95 % CI 0.77–0.95)  Table , with anp = <0.001).Because it may be arguable as to what cutoff points of increase in SVI is truly clinically meaningful, we calculated ROC curves of the main indices taking an increase in SVI >10 %, instead of >15 % as cutoff. The results were similar, as ΔCDPV maintained the greatest AUROC , notwithstanding pre-challenge SVI was not different . As seen in Table p = 0.29) or ΔCDPV (p = 0.32). Median in time between fluid challenges per patient was 4 h (IQR 3.2–5). The presence of acute respiratory distress syndrome or acute kidney injury was not associated with a lack of response to fluid challenge. There was no newly detected carotid stenosis or diminished ejection fraction. The mean time to obtain ΔCDPV was 54 s .Responders had a significantly higher median rise in the SVI after the fluid challenge compared to non-responders . A regression formula for predicting a rise in the SVI after fluid challenge was obtained . There was no significant correlation between the other indices and change in the SVI.Only ΔCDPV was positively correlated with a fluid challenge-induced change in the SVI, and ΔCDPV had the highest correlation coefficient  for assessing fluid responsiveness in mechanically ventilated patients with septic shock. Furthermore, the ΔCDPV has a high correlation with SVI increase after fluid challenge. To our knowledge, this is the first investigation that utilizes the ΔCDPV as a predictor of fluid responsiveness in patients with lung protective mechanical ventilation and septic shock.In our study, up to 40 % of the patient population had technically difficult echocardiographic apical views, which limited the measurement of the velocity time integral at the left ventricle outflow tract. Hence, alternative non-invasive and practical methods for assessment of fluid responsiveness in septic shock should be investigated. This is a limitation of point-of-care echocardiography in the ICU because the procurement of different acoustic windows varies and presents different degrees of difficulty for mastery . MoreoveOther authors have explored the applicability of echocardiography in mechanically ventilated patients. Feissel et al.  reportedMonge Garcia et al.  demonstrr = 0.84 versus r = 0.63) [The preferential diversion of blood flow toward the carotid arteries, away from the peripheral arteries, is a relevant pathophysiological consideration in patients suffering from shock . Conside = 0.63) . This fiRecently, Marik et al.  evaluateThere has been a recent interest in the response to fluid administration over time in patients with shock. Nunes et al.  highlighThe performance of PPV and SVV for prediction of fluid responsiveness has been previously reported, with both sensitivity and specificity higher than 90 % , 30. HowThis study has some limitations. As a respirophasic dynamic index, ΔCDPV does not apply to patients with spontaneous breathing, arrhythmias, valvular disorders, significant heart failure, and common carotid stenosis. Nonetheless, measurement of ΔCDPV is a reliable method, without the inherent risk of central artery cannulation, which is present for thermodilution or pulse contour analysis systems. Additionally, there is no need to raise the patient’s legs, which is a time-consuming maneuver. Further, it is discouraged and/or unreliable in postsurgical, abdominal hypertension, or fractured patients. We performed point-of-care echocardiography to address ejection fraction in all patients. However, we did not record the ratio of early transmitral flow velocity to the early diastolic velocity of the mitral annulus (E/E'); therefore, the incidence of elevated left ventricular filling pressures was unknown. This could be a possible bias in the study, as an elevated E/E’ (>15) is negatively correlated with lower performance at prediction of fluid responsiveness , 36. In Although the reliability of PiCCO system has been found to be good in heterogeneous groups of patients, it is still questioned, mainly on the time-dependent accuracy on recalibrations and its variability on agreement at different vasopressor dose , 37, 38.External validity is limited, as physicians involved at estimation of ΔCDPV were trained in critical care sonography for more than 1 year. Also, due to the observational nature of the study, management was not ΔCDPV-guided, and the spectrum of patients was narrow, including septic shock patients only. As long as there are clinical trials addressing these issues, our results should be interpreted cautiously. For statistical comparison between ROC curves with the Hanley–McNeil test, “measurements” are required. Therefore, we do not consider the relatively small sample size to be a limitation of our study.In this single-center study, we showed that ΔCDPV could be more accurate than other methods for assessing fluid responsiveness in patients with septic shock receiving lung protective mechanical ventilation. The ΔCDPV also has a high correlation with SVI increase after fluid challenge.


Hemigrapsus sanguineus and Carcinus maenas, in the Long Island Sound (LIS), we deployed artificial shelters in the intertidal and immediate subtidal zones. These consisted of five groups during the summer: a control, a resident H. sanguineus male or female group, and a resident C. maenas male or female group. We quantified utilization of the shelters at 24 h by counting crabs and fish present. We found significant avoidance of H. sanguineus in the field by benthic hermit crabs (Pagurus spp.) and significant avoidance of C. maenas by the seaboard goby (Gobiosoma ginsburgi). The grubby  avoided neither treatment, probably since it tends to be a predator of invertebrates. H. sanguineus avoided C. maenas treatments, whereas C. maenas did not avoid any treatment. Seasonal deployments in the subtidal indicated cohabitation of a number of benthic species in the LIS, with peak shelter use corresponding with increased predation and likely reproductive activity in spring and summer for green crabs (C. maenas), hermit crabs (Pagurus spp.), seaboard gobies (G. ginsburgi), and grubbies .To investigate community shelter effects of two invasive decapod species,  These species are competitors for space and food with native species , for a total of five treatments; and (2) use these deployments and complementary laboratory studies (to better explain any effects of C. maenas and H. sanguineus on one another) to predict which LIS community species found in our shelters will be most affected by the presence of one of these invaders.Our main objectives for this study were to: (1) capture any sexual variability in shelter use by decapods, as described above for other decapods, which was accomplished through a field experiment with empty PVC artificial shelters as a control, and a male and female treatment for each of the two types of crab . Replicates of the field apparatus  were depWe took two approaches: (1) to capture animals that may only be using subtidal shelters seasonally, we deployed the artificial shelters four times over the course of a year; (2) In order to gain a sense for the intertidal use of shelter, which is most used in the summer months in the LIS, we also deployed intertidal experimental artificial shelters during the summer.Hemigrapsus sanguineus in the intertidal system, we wanted to see the overall effect on community shelter use across four seasons for this species in the subtidal zone. These shelters were deployed subtidally (∼1 m depth) across four seasons in 2009, with control, and live male and female H. sanguineus bait treatments .Due to dominance of Carcinus maenas bait treatments were added. Thus, five treatments were used, along with the same control, live male and live female H. sanguineus treatments as already deployed in the seasonal deployment. We deployed the artificial shelters both in the subtidal and in the intertidal zone. As such, for summer experiments, each treatment was deployed in replicates of 60 both subtidally and intertidally . A two-way ANOVA with tidal deployment and treatment was used to determine the interaction between treatment and tidal deployment, and size differences between subtidal and intertidal deployments were analyzed with Student’s t-test.In the summer months two additional treatments; live male and live female H. sanguineus and C. maenas. Multiple carapace width ratios, approximately 3:1, 2:1, 1:1, 1:2, and 1:3 in replicates of 10, were used for a one-on-one laboratory shelter competition experiment that lasted 24 h. We compared intraspecific (H. sanguineus or C. maenas versus member of the same species) and interspecific (H. sanguineus versus C. maenas) competition trials. Shelter use frequency differences between competitors were analyzed using Fisher’s Exact Test. The effect of size ratio of competitors on “winner” and mortality was analyzed by a linear regression in R statistical software. Crabs were introduced to a plastic 18 × 31 cm arena with 2.5 cm of sand substrate and a 10 × 5.0 cm shelter made from 6.35 cm PVC pipe with a quarter of its circumference removed arranged in the container to have only one useable opening , the seaboard goby Gobiosoma ginsburgi, and the grubby Myoxocephalus aenaeus. Subtidal deployment caught very few Hemigrapsus sanguineus individuals . Seasonal change in shelter use  occurred amongst the four most collected species . However, significant seasonal shelter usage changes were observed in C. maenas . Spring shelter usage was nearly triple that of winter , which then significantly  dropped by 54% in the summer deployment  .No significant difference  was seen for ployment . C. maen values) . When alGobiosoma ginsburgi , with spring shelter usage 23 times that of winter, then a subsequent significant dip during the summer by about one third, and further dip from spring values during autumn to about 11 percent shelter use . The seainsburgi  showed a aenaeus  significPagurus spp. showed preference for treatments , specifically avoiding both H. sanguineus male and female treatments  in the subtidal  by avoiding completely  both of the C. maenas treatments  for any treatments, and was found at lower catch rates  than subtidal shelter use by a factor of about 3.6 times  subtidal shelter use (1% use at 3 crabs in 300 shelters) than intertidal shelter use (14% use at 42 crabs in 300 shelters)  . No compH. sanguineus behavior were observed. H. sanguineus males used shelters of any treatment 8.3% of the time (N = 301 shelters), but used intertidal treatments differently . Males displayed a lower (3.3% of treatment shelters) use of C. maenas male  and C. maenas female  treatments  when compared to the 16.9% use of H. sanguineus female treatment shelters , but across all treatments only used 4.65% of them (N = 301 shelters). Female H. sanguineus crabs  when compared with the control 11.7% usage rate . There were no significant differences for other treatments, perhaps due to females’ low shelter usage rate.In the summer intertidal experiments, differences in male and female shelters . Female us crabs  did not H. sanguineus . In intertidal treatments, H. sanguineus showed no significant reduction in shelter use of either H. sanguineus treatments over control (cage only) treatment , sticking at 25% (15/60) use for control shelters, 8.33% (5/60) use for H. sanguineus male treatments, and 25.4% (15/59) use for H. sanguineus female treatments. The greater usage of H. sanguineus female shelters over all other crab treatment shelters is significant . However, H. sanguineus did significantly decrease use of C. maenas female treatment shelters to 4.84% (3/62) , and trended  to decrease  use of C. maenas male treatment shelters .When pooled regardless of sex or maturity, significant differences were found in use of intertidal treatments by shelters . When suH. sanguineus is more likely to use shelter than C. maenas  (H. sanguineus utilized (“won”) shelter 32.8% of the time, whereas C. maenas only utilized shelter 9.1% of the time. While this comparison is interesting on its surface, intraspecific competition puts this in context. When C. maenas competes against an individual C. maenas, one of the crabs utilizes the shelter 20.1% of the time (N = 29), which is not significantly different than its 9.1% shelter from when it was competing against H. sanguineus . The same result is observed for H. sanguineus, which uses shelter at 33.3% rate (N = 39) when competing against another H. sanguineus, which is also not significantly different in its shelter use from when it was competing against C. maenas . When analyzed by the effect of competitor size , but C. maenas’ use of shelter was not significant by linear regression (p = 0.49). When crabs of the same approximate size are compared , H. sanguineus is significantly more likely to end up in the shelter than C. maenas in interspecific trials . However, neither is more likely to be injured or die when evenly matched by size. In interspecific trials, both H. sanguineus and C. maenas were killed more often when they were smaller than the opposing crab ), and 67% of that in C. maenas death rates ). C. maenas and H. sanguineus both exhibit cannibalism when large differences in carapace width exist  . In intetor size , H. sanging crab , and linxist see , and reaMyoxocephalus aenaeus and Pagurus spp. shelter competition with these decapods may have a greater impact during spring and summer months. Decapods Carcinus maenas and the Pagurus spp. complex showed peak shelter use in the spring deployments, and both of the fish species (Gobiosoma ginsburgi and M. aenaeus) peaked during summer. Other Gobiosoma spp. exhibit seasonal patterns in shelter use, primarily with an increase in use of seagrass shelter in July and October , shrimp Palaemontes spp. (11 collected), Crangon septemspinosa (5 collected), Cancer irroratus (5 collected), Panopeus herbstii (21 collected), Dyspanopeus sayi (9 collected), Xanthid crab settlers (8 collected), Pholis gunnelus (1 collected), Anguilla rostrata (4 collected), Littorina littorea (17 collected), and the cunner Tautogolabrus adspersus (17 collected). These collected species could just be in lower numbers, not typically use shelter (not likely for the crab species), or be adversely affected by the presence of the two crabs. Determining the proximal cause requires further comparative work, but in the Gulf of Maine, both Hemigrapsus sanguineus and C. maenas make intertidal shelter maladaptive for native species .When ier work . Thus, oorelines . This adH. sanguineus shows avoidance of potentially dangerous heterospecifics (C. maenas of both sexes) and conspecific male shelters and a preference for conspecific female shelters and unoccupied control shelters. This may enhance H. sanguineus’ survival and reproduction through avoidance of antagonistic interactions like predation and competition, and indicates it can detect and use conspecific and heterospecific presence as an adult in addition to as a megalopa  Summer intertidal deployment of multiple treatments . (C) Summer subtidal deployment in C. maenas. Significance between treatments or deployment depth indicated by: “*” = p < 0.05, “**” = p < 0.01, “***” = p < 0.001.Catch per unit effort ) mean ± SE. (A) Click here for additional data file.10.7717/peerj.2265/supp-3Supplemental Information 3Stated in catch per unit effort  mean ± SE. Significance between deployment depth indicated by: “*” = p < 0.05, “**” = p < 0.01, “***” = p < 0.001.Click here for additional data file.


The rise of social media and microblogging platforms in recent years, in conjunction with the development of techniques for the processing and analysis of “big data”, has provided significant opportunities for public health surveillance using user-generated content. However, relatively little attention has been focused on developing ethically appropriate approaches to working with these new data sources.Based on a review of the literature, this study seeks to develop a taxonomy of public health surveillance-related ethical concepts that emerge when using Twitter data, with a view to: (1) explicitly identifying a set of potential ethical issues and concerns that may arise when researchers work with Twitter data, and (2) providing a starting point for the formation of a set of best practices for public health surveillance through the development of an empirically derived taxonomy of ethical concepts.We searched Medline, Compendex, PsycINFO, and the Philosopher’s Index using a set of keywords selected to identify Twitter-related research papers that reference ethical concepts. Our initial set of queries identified 342 references across the four bibliographic databases. We screened titles and abstracts of these references using our inclusion/exclusion criteria, eliminating duplicates and unavailable papers, until 49 references remained. We then read the full text of these 49 articles and discarded 36, resulting in a final inclusion set of 13 articles. Ethical concepts were then identified in each of these 13 articles. Finally, based on a close reading of the text, a taxonomy of ethical concepts was constructed based on ethical concepts discovered in the papers.From these 13 articles, we iteratively generated a taxonomy of ethical concepts consisting of 10 top level categories: privacy, informed consent, ethical theory, institutional review board (IRB)/regulation, traditional research vs Twitter research, geographical information, researcher lurking, economic value of personal information, medical exceptionalism, and benefit of identifying socially harmful medical conditions.In summary, based on a review of the literature, we present a provisional taxonomy of public health surveillance-related ethical concepts that emerge when using Twitter data. Since its inception in 2006, the microblog platform Twitter has become a key resource for understanding—and sometimes predicting—mass behavior, particularly in the area of marketing  and poliWhile there has been significant research effort in developing ethical guidelines for conducting Internet discussion forum-based research generally  and for In this review, we are focused on exploring ethical issues that have been identified in published Twitter-based public health surveillance research papers. Relevant research is dispersed across several broad research areas, including biomedicine (Medline), computer science and engineering (Compendex), philosophy (Philosopher’s Index), and psychology (PsycINFO). As we are primarily interested in ethical and regulatory issues and how they relate to public health surveillance, with the aid of a biomedical librarian, we designed a complex set of queries for each indexing service to identify those papers that included ethics-related terms in their titles or abstracts, such as “IRB” , “ethics”, and “privacy”. See As the focus of this review is on ethical issues in large-scale automatic Twitter-based research for public health surveillance, we excluded work centered on non-microblog social media platforms . We also excluded work on policy and clinician/student professionalism , and research focused on non-health related topics  with the exception of those articles concentrating on automatically identifying personality variables from Twitter feeds.After searching the four databases with queries shown in Our initial set of queries identified 342 references across the four databases see . After tOur iterative, taxonomy construction process identified 10 broad ethical categories . Six of these categories included several subcategories . The most prevalent and complex ethical category we found was privacy with 16 subcategories covering such important ethical concepts as unintended revelation of personal information and population level monitoring vs individual diagnosis . MultimePrivacya. Concept of privacyi. Public vs private - doubts about the location of Twitter data on the public/private spectrum ,18,21,24ii. Fluidity in the concept of privacy - rapidly changing concept of privacy ,18,21,24iii. Generational differences in the concept of privacy ,18iv. Panopticon effect - risk that public health monitoring will change user behavior on Twitter b. Confidentialityi. Data linkage - risk of privacy loss due to linking data from different sources ,21ii. Confidentiality - appropriate storage of Twitter data by researchers iii. Right to/desire for anonymity - research using Twitter challenges a participant’s right to (and desire for) anonymity ,14,16c. Stigmatized medical conditions - concerns about protecting the privacy of those with stigmatized medical conditions  ,20d. Twitter’s privacy policy - implications of Twitter’s privacy policy and how it is understood by users ,19,21,22e. Twitter is publicly accessible by default - emphasizes that Twitter is a broadcast medium. Unless a user changes privacy settings, tweets are public ,21,22,24f. Reliability of user provided personal details - reliability of information derived from Twitter when some users use false or whimsical personal details to maintain anonymity ,21,24g. Interpreting decontextualized Twitter data as fully representative of users who are in fact multifaceted - possibility that the user might be experimenting with self-presentation or exhibit a belief or behavior in their historical tweets that they no longer adhere to  ,24h. Unintended revelation of personal information - potential for a user to unintentionally provide insights into their mental health, health behaviors, etc, through information garnered from their tweets ,22-24i. Personal responsibility of Twitter users - emphasizes the responsibility users have for their posts ,24j. Twitter users have no expectation of privacy - emphasizes the researchers’ belief that Twitter users have no reasonable expectation of privacy ,21k. Identifying users’ mental health status or personality traits to:i. identify those in need of treatment ,25ii. job placement ,22-24iii. targeted marketing ,23iv. system interface design  ,23v. law enforcement  l. Population level monitoring vs individual diagnosis - difference between using Twitter to identify broad, population level changes and diagnosing individuals m. Potential for discrimination based on health status as garnered from social media n. Danger of inaccurately labeling a user as suffering from a particular health problem ,22o. Traceability of Twitter data - risk that tweets can be traced back to the original tweeter if reproduced verbatim in research work, threatening anonymity ,17p. Intended audience for tweets - some Twitter users use Twitter as a communication tool for a small group of family and friends and do not expect their tweets to be widely read . Other Twitter users aim to broadcast to the world and gain the maximum number of followers ,21,24Informed Consenta. Twitter users are oblivious or unwilling research participants b. Informed consent is difficult (or impossible) to gain (or not required) for large-scale Twitter work ,14,24Ethical Theorya. Difficulties in applying current ethical theories to mass Twitter research b. Ethical theories:i. Deontology ,26ii. Utilitarianism ,26iii. Feminism iv. Communitarianism v. Application of the “golden rule” vi. Agile/situational ethics vii. Rawls’ theory of justice IRB/Regulationa. Citizens’ rights to communicate and share information ,26b. Researcher belief that regulatory oversight is not required when using Twitter data c. Discussion of IRB/ethics committees, generally ,18d. Data protection legislation ,18e. Professional codes of conduct f. Need for regulatory control, generally ,20g. Privacy regulation by country ,24Traditional research vs Twitter researcha. Apomediation - shifting from hierarchical models of research to a situation where the researcher is a potential participant b. Scale of Twitter-based research - research norms that were developed for small-scale research do not scale to millions of Twitter users c. Greater distance between researcher and participants - mass Twitter-based research increases the distance between researchers and participants d. Ambiguous status of participants - the status of participants is more ambiguous than in traditional research  e. Increase in researcher power - in mass Twitter research, a single researcher has access to millions of Twitter users, hence increasing researcher power Geographical Informationa. Tracking physical location - potential loss of privacy in tracking Twitter users’ physical locations ,14,19,21somewhere in Los Angeles is very different to reporting their precise location in Los Angeles [b. Appropriate geographical granularity – potential loss of privacy in reporting a Twitter user’s precise location, compared to their general location. For example, reporting that a Twitter user is  Angeles Researcher Lurking ,14Economic Value of Personal Information Medical Exceptionalism - health-related matters are qualitatively different from other, non-medical areas and require special attention (and perhaps regulation) Benefit of Identifying Socially Harmful Medical Conditions discussed but not necessarily endorsed.In several of the papers under review, explicit normative rules were presented (or suggested) for conducting and reporting mass Twitter public health surveillance work . Note thWhen reporting research, avoid quoting directly from users’ Twitter streams. Paraphrases should be used .Informed consent should be gained from participants .Metadata  should not be disclosed .Twitter-based work is human subjects research and requires that some form of appropriate IRB/ethical review take place .Data collection should be logged and justified .There should be parity between the researcher and participants  .Employment-related profiling for mental health conditions should only be performed in exceptional circumstances  .Consent should be gained from potential employees before employment-related profiling for mental health conditions is performed .The main output of this research is a taxonomy of ethical concepts derived from close reading of the literature. The taxonomy will be used to help frame future interview-based qualitative research focused on Twitter users’ attitudes to the use of microblog data for public health surveillance and, in due course, inform the generation of a set of ethical guidelines for using Twitter for public health surveillance and research. We found that ethical theory was rarely mentioned in the reviewed papers and, when it was discussed, that discussion was typically brief. Only two papers ,26 expliclose reading in place of a theoretically grounded qualitative methodology. A further characteristic of this review is that our search strategy was confined to papers indexed in PubMed, Compendex, PsycINFO, and the Philosopher’s Index. Papers that were not available via the University of California San Diego library system or on an open-access basis were excluded. It is likely that we “missed” relevant papers in business disciplines or in those computer science and engineering conferences and journals not indexed by Compendex. However, our purpose in this review was the identification of a broad taxonomy of ethical concepts relevant to Twitter-based public health research using a systematic, reproducible methodology and thus comprehensiveness, while desirable, is not a necessity.Although inspired by the ethics-oriented qualitative literature review methodology proposed by Strech , the appIn conclusion, this short paper provides a taxonomy of ethical concepts derived from the research literature. Future work will involve interview-based qualitative research exploring Twitter users’ attitudes toward the mining of their data for public health purposes, and ultimately the formation of best practice guidelines for public health surveillance using Twitter data.


Introduction. Varicella zoster virus (VZV) encephalomyelitis with cranial nerve involvement is rare. Characteristically it is preceded by a rash and primarily presents in the immunocompromised. The spectrum of VZV neurologic disease is extensive and it is not uncommon to present without rash. We report the case of an elderly otherwise immunocompetent patient who presented with diverse manifestations of VZV CNS infection all occurring without rash. Case Report. A 78-year-old man presented with 1 week of progressive paraparesis and sensory loss, malaise, and fevers. MRI of the neuraxis demonstrated numerous enhancing lesions: intramedullary, leptomeningeal, pachymeningeal, and cranial nerves. Cerebrospinal fluid (CSF) showed a white blood cell count of 420/μL with elevated protein (385 mg/dL). CSF VZV qualitative PCR was positive and CSF VZV immunofluorescence assay detected IgM antibody, confirming the diagnosis of VZV encephalomyelitis. Clinical and radiological improvement was observed after intravenous acyclovir treatment. Conclusion. This is a rare report of an immunocompetent patient with extensive VZV encephalomyelitis. We highlight the importance of considering this diagnosis even in the absence of the characteristic rash, and the potential risk of premature discontinuation of antiviral therapy once HSV has been excluded. Prompt recognition and treatment can dramatically reduce morbidity and mortality in patients. Reactivation of VZV classically presents with herpes zoster (shingles), characterized by pain with an accompanying rash in a dermatomal distribution. However, involvement may extend anywhere along the neuraxis, including the brain , cranial nerves , cerebellum, spinal cord, and meninges . A rash VZV encephalomyelitis is rare and was traditionally thought to be seen primarily in the immunocompromised patient; however, there have been increasing numbers of this disease entity involving immunocompetent patients as more clinicians utilize CSF PCR and serology to confirm this diagnosis . To dateA 78-year-old man with hypertension and hyperlipidemia presented with a 2-week history of urinary urgency and frequency. Over the next 1 week, he began to experience malaise, headache, otalgia, fever, lower back pain, and bilateral lower extremity weakness with difficulty ambulating and was admitted to his local hospital. He denied sick contacts, rash, or tick bites.On presentation he had a normal mental status and cranial nerve examination. Pertinent findings noted were diminished sensation to temperature and vibration in the left L5 distribution, impaired proprioception at the toes bilaterally, and areflexia throughout. He had full strength in all extremities. Coordination was intact on finger to nose and heel to shin testing; however, the gait was wide and unsteady.μL and protein of 633 mg/dL. Glucose and red blood cell counts (RBC) were within normal range. Gram stain and routine bacterial cultures were negative.White blood cell count (WBC) was 12 K/uL. CT and MRI/MRA head were consistent with chronic microangiopathy of the deep white matter and an incidental finding of a right middle cranial fossa arachnoid cyst. CSF profile was noted for a WBC of 115/One week into his hospital course, his symptoms progressed resulting in right leg plegia, left lower extremity paresis , and decreased anal tone; his upper extremity strength remained intact. He was subsequently transferred to our main university teaching hospital for further work-up.Further investigations at our facility comprised of serologies, imaging, CSF, and nerve conduction studies (NCS). Preliminary investigation showed angiotensin converting enzyme and a rheumatologic panel to be negative. Infectious disease work-up testing for Lyme, HIV, chlamydia, gonorrhea, syphilis, and tuberculosis was also negative. Immunologic testing was not performed in this case as the patients' medical history and preliminary blood work did not suggest an immunocompromised state. NCS of the lower extremities revealed a sensorimotor axonal polyneuropathy in the lower extremities.MRI of the brain and thoracic and lumbar spine with and without gadolinium was performed. The thoracic and lumbar T1 postcontrast images revealed numerous foci of intramedullary enhancement, including some that were ring enhancing. There was also enhancement of the leptomeninges including the cauda equine . Axial TμL , RBC 10, protein 385 mg/dL, and glucose 47 mg/dL. This was felt to be consistent with an aseptic meningitis, and empiric IV acyclovir 10 mg/kg three times daily was started to treat possible viral etiologies. CSF studies including PCR for Lyme, CMV, EBV, herpes simplex virus (HSV) type 1 (HSV1), HSV 2, human herpes virus 6 (HHV6), and West Nile virus were negative. CSF ACE was within normal limits and CSF VDRL was nonreactive. CSF VZV qualitative PCR was found to be positive and quantitative PCR yielded 1.56 × 104 copies/mL. CSF VZV immunofluorescence assay detected VZV IgM antibody . A diagnosis of VZV encephalomyelitis was confirmed and IV acyclovir was continued.Repeat lumbar puncture (LP) yielded the following results: WBC 420/During the hospital course the patient showed improvement of the right iliopsoas strength to a medical research council (MRC) grade 3/5 and increased sensation to fine touch in the bilateral lower extremities. However, global areflexia as well as impaired proprioceptive and vibratory sensation in the lower extremities persisted. Additionally, he developed new symptoms of vertical diplopia, and right cranial nerve IV palsy was diagnosed. The patient was discharged to a rehabilitation facility where he completed a 6-week course of IV acyclovir. At his 2-month follow-up appointment, he had significant improvement of his lower extremity strength and was able to ambulate with a walker. Repeat MRI of the thoracic and lumbar spine showed improvement of the intramedullary lesions, both in number and size . The enhVZV reactivation typically occurs in the immunocompromised host and more commonly this reactivation produces herpes zoster (shingles), resulting in characteristic pain, with or without a rash, in a dermatomal or cranial nerve distribution. While CNS involvement is now considered rare, prior to the introduction of the childhood vaccine in 1995, VZV was reported to be the most common agent associated with acute CNS disease of viral origin—specifically encephalitis, meningitis, and myelitis—followed by herpes simplex virus (HSV), enteroviruses, and influenza A virus . In a reDistinguishing clinically between VZV and HSV encephalomyelitis can be difficult, particularly in the absence of a rash; therefore, certain radiographic findings may be helpful. Radiographic findings of VZV CNS involvement can be extensive, with reports of abnormal T2 hyperintense lesions (with and without gadolinium enhancement) in the brain, spinal cord, and cranial nerves, and diffusion weighted abnormalities due to brain and spinal cord infarctions , 11. VZVP < 0.001 [4 CSF viral copies had more severe neurologic manifestations of VZV infection, specifically meningitis and encephalitis [4 copies by quantitative PCR, and detection of anti-VZV IgM antibodies in the CSF confirmed the diagnosis in our patient.Virological confirmation is necessary for a diagnosis. Recommended tests included detection of VZV DNA in the CSF , anti-VZV IgM antibody (serum or CSF), and/or anti-VZV IgG antibody in the CSF. Most people have anti-VZV IgG antibody in the serum, and therefore this test is of little clinical value. Detecting anti-VZV IgG antibody in the CSF, however, is a more sensitive indicator of CNS involvement compared to detection of VZV DNA by PCR . One stu < 0.001 . Given t < 0.001 . Aberle phalitis . The detCurrent guidelines from the Advisory Committee for Immunization Practices (ACIP) recommend a routine single dose of zoster (shingles) vaccine for adults aged 60 years and older, to prevent herpes zoster and postherpetic neuralgia . IncidenThis case emphasizes the fact that VZV reactivation can have extensive CNS involvement in an elderly but otherwise immunocompetent individual, without an accompanying rash. We highlight the importance of considering VZV as a possible cause for encephalomyelitis in the elderly and the recommended laboratory diagnostic testing. A potential pitfall for clinicians is the premature discontinuation of antiviral therapy once HSV has been excluded. Prompt recognition and early treatment can result in significant improvement—both clinically and radiographically—as was observed in our patient, thereby preventing severe or potentially fatal consequences of a disseminated VZV CNS infection.


Acute kidney injury (AKI) is defined as oliguria or rise in serum creatinine but oliguria alone as a diagnostic criterion may over-diagnose AKI.Given the association between fluid overload and AKI, we aimed to determine if positive fluid balance can complement the known parameters in assessing outcomes of AKI.Prospective observational study.Teaching hospital in Vancouver, Canada.111 consecutive patients undergoing elective cardiac surgery from January to April 2012.Outcomes of cardiac surgery intensive care unit (CSICU) and hospital length of stay (LOS) in relation to fluid balance, urine output and serum creatinine.All fluid input and output was recorded for 72 hours post-operatively. Positive fluid balance was defined as >6.5 cc/kg. Daily serum creatinine and hourly urine output were recorded and patients were defined as having AKI according to the AKIN criteria.Of the patients who were oliguric, those with fluid overload trended towards longer LOS than those without fluid overload . Patients with oliguria who were fluid overloaded had similar LOS to patients with overt AKI (change in serum creatinine ≥ 26.5 µmol/L), [CSICU LOS: 62 and 69 hours  and hospital LOS: 13 and 14 days ]. Patients with oliguria regardless of fluid balance had longer CSICU LOS  and patients who were fluid overloaded in the absence of AKI had longer hospital LOS .Single centre, small sample, LOS as outcome.Oliguria and positive fluid balance is associated with a trend towards longer LOS as compared to oliguria alone. Fluid balance may therefore be a useful marker of AKI, in addition to urine output and serum creatinine. Oliguria as a sole diagnostic criterion may over-diagnose acute kidney injury.Considering oliguria in the context of fluid status may be more useful than using oliguria as a sole diagnostic criterion. This study suggests that oliguria in the context of fluid overload identifies patients who require a longer length of stay as compared to patients who have oliguria alone.Acute kidney injury (AKI) describes a spectrum of conditions ranging from a biochemical abnormality to oligoanuric renal failure requiring renal replacement therapy. It is associated with adverse short and long term outcomes in all populations studied, irrespective of the definition used. The definitions have varied over time in the published literature as well as in clinical practice. Recently published, standardized definitions from the KDIGO AKI Guideline  include AKI as defined by the Acute Kidney Injury Network (AKIN)  is basedAlthough reduced urine output often precedes development of AKI as defined by a rise in serum creatinine, oliguria as a sole diagnostic criterion has been questioned by many as being too sensitive, and classifies too many people as having ‘AKI’ . There iFluid balance or evidence of fluid overload has come to the attention of both clinicians and researchers as an alternative ‘biomarker’ for AKI. Fluid overload has been associated with adverse outcomes in critical care populations, and is often seen in association with AKI. There has been an ongoing ‘chicken and egg’ debate  regardinThe current study sought to describe the individual parameters of fluid balance, urine output and changes in serum creatinine in varying combinations, in a population of patients undergoing elective cardiac surgery. We were interested in describing the constellations of these 3 parameters and their association with outcomes in this specific population.The hypothesis of the study is that fluid balance is a useful parameter for the identification of patients - broadly diagnosed with AKI – who have worse outcomes.One hundred and eleven consecutive patients who were undergoing elective coronary artery bypass grafting (CABG), valve replacement or combined surgery over a 3-month period from January and April 2012 (convenience sample) were prospectively enrolled in this observational study. Patients on dialysis, those undergoing off pump surgical procedures, trans-catheter valve replacement surgery and isolated or combined thoracic aorta surgery were excluded.Demographic and clinical baseline characteristics and risk factors were obtained from medical records and included: age, sex, weight, presence of diabetes, serum creatinine, eGFR (MDRD equation) <60 ml/min/1.73 m , exposurPatients were observed and data tabulated for all fluid inputs and outputs for 72 hours post operatively, irrespective of location of the patient . Fluid balance was determined from all records upon discharge from the cardiac surgery intensive care unit (CSICU) and expressed as cc/kg. Daily serum creatinine and body weight was also recorded.Cr)) was an increase from baseline of ≥26.5 µmol/L and the definition based on urine output (AKIUO) was urine output ≤ 0.5 cc/kg/hour for greater than 6 hours. We defined positive fluid balance for the purposes of this study as ≥ 6.5 cc/kg based on the rationale that insensible losses per day are approximately 500 cc/day. Thus, using the mean weight in the population (81 kg), we calculated that 6.5 cc/kg would approximate insensible losses (525 cc) over one day – the median CSICU length of stay – so that amounts over that would constitute a positive fluid balance.For the purposes of this study we defined AKI as per the AKIN criteria: the definition of AKI based on serum creatinine , urine output  and fluid balance . The combinations under consideration were: 1) SCr-, UO-, FOL- (no AKI), 2) SCr-, UO-, FOL+, 3) SCr-, UO+, FOL-, 4) SCr-, UO+, FOL+, and 5) SCr +.The main outcomes of interest were duration of CSICU (hours/days) and hospital length of stay (LOS) (days).Continuous variables are presented as mean with standard deviation if normally distributed or median with interquartile range. Frequencies and percentages were presented for categorical variables.The comparisons on the demographics, preoperative and intraoperative measures across groups were conducted using One-way ANOVA, Kruskal-Wallis test, Chi-square or Fisher’s exact tests where appropriate.We wanted to treat the group variable as an ordinal variable as these group variables reflected severity as seen in Figures 3 (comparing group 3 and 4) was statistically significant, this would imply there were no differences in the mean log(LOS) in the first 3 groups and that furthermore, there was also no difference in the mean log(LOS) in the last 2 groups; hence group 4 was the critical breakpoint for an increase/decrease in the outcome.We could then compare between any two adjacent categories and hence obtain the best estimate of the increment/decrement  in the mean outcome between any two adjacent categories from the data. In other words, this would allow us to identify the ‘breakpoint(s)’ or ‘threshold(s)’ of the group variables at which significant changes occur in the outcome. For example, if only βThe relationships between various combinations of change in serum creatinine/urine output/fluid balance and outcomes were examined by fitting two separate models, one for CSICU LOS and one for hospital LOS. Each LOS outcome was assumed to be log-normally distributed. We fitted a multiple linear regression model to examine the association between mean of log(LOS) and groups adjusting for potential confounding variables. The group variable (ie: combination of SCr/UO/FOL status) was parameterized  as in TaWe adjusted for the covariates age, diabetes status, preoperative eGFR, duration of surgery, CPB time, blood transfusion and vasopressor requirement and percentage of patients with negative fluid balance during the intraoperative phase (only for CSICU LOS) in the models. These covariates were included based on clinical and statistical judgment on their relations to both group and outcome variables which resulted in the best fit to the data.We considered a p-value of <0.05 as statistically significant. All statistical analysis was performed using SAS, version 9.3 .The study was approved by the institutional review board  and conformed to the regulations of the institutional ethics committee on human research. Written consent was not required due to the observational nature of the study, and lack of interventions.Table The median duration of surgery was 177 minutes with a median CPB time of 92 minutes. 22% received intraoperative blood transfusion, and the median total fluid administered intraoperatively was 1850 cc. At the end of surgery, the median total fluid balance measured was positive 1269 cc, while 7% of patients had a negative balance at completion. Intraoperative urine output was less than 500 cc in all groups.Cr was 9% (n = 10) and AKIUO was 31% (n = 35). Of those with AKICr, 9/10 also met urine output criteria. Figure UO) and SCr + (AKICr). Note that those with AKICr had the largest proportion of positive fluid balance (>6.5 cc/kg), and those with AKI by either definition had larger proportion of positive fluid balance than those who did not have AKI using either parameter.Using the accepted definitions of AKI, the incidence of AKIThe median intensive care unit LOS was 24  hours.Figure and fluid overload  to those with oliguria alone , there was an estimated increase in mean log(LOS) of 0.35 . In the adjusted analyses, the only difference remained was between those with and without oliguria (estimated increase in mean log(LOS): 0.44 ; p-value = 0.001).Table The median hospital LOS for the population was 9  days.Figure Cr when compared to oliguric patients with fluid overload : the estimated increase was 0.36 .In the unadjusted analyses , 30 cc/kg equates to approximately 2 litres, after accounting for insensible losses.The change in serum creatinine, fluid balance and weight gain in each of the different categories is described in the lower panel of Figures and fluid overload had trends towards longer LOS in both CSICU and in hospital. The value of ‘contextualizing’ urine output by including a measure of overall fluid balance has not been overtly discussed in any of the recent guideline proposals.This study describes the outcomes for patients undergoing elective cardiac surgery who develop AKI, using various definition parameters. We used an integrated categorization of AKI that incorporates both the AKIN criteria and fluid balance. We wanted to demonstrate the merits of considering each parameter - serum creatinine, urine output and fluid balance - together, as they are associated with the relevant outcomes of CSICU and hospital LOS. Our data suggests a potential difference in LOS for cardiac surgery patients with AKI as defined using these different parameters in various constellations. In those patients with oliguria, there was an increased duration of CSICU LOS, but those with oliguria Since oliguria as a sole diagnostic criterion for the diagnosis of AKI has been considered oversensitive, we suggest that in the context of fluid overload it may in fact portend worse outcomes (defined here as longer LOS). Some publications suggest that the current criterion of ≤0.5 cc/kg/hour for greater than 6 hours may identify patients who are at no greater risk of mortality or need for dialysis ,9. This UO is imperfect as only a small number of patients with AKIUO subsequently develop AKICr [Although AKIop AKICr , reductiop AKICr . Use of op AKICr  in hospiConcealed AKI as a result of dilution of creatinine by volume expansion has been recognized -16 as a The mechanism by which fluid overload may cause increased mortality is multifactorial . IntraveUO or AKICr had more positive fluid balance than those without AKI, again consistent with other studies [Patients in our study with either AKI studies ,21. Flui studies  of cardi studies  and mort studies . We did There are limitations to this study. This is a single centre study, using a convenience sample of consecutive patients undergoing elective surgery. The outcomes are limited to short term , and not to 30 day mortality or peri-operative complications, as in other studies. However, the purpose of the study was to describe AKI according to the different criteria, and determine if those definitions had relevance to LOS. It is important to acknowledge that prolonged LOS is an important outcome from an individual patient and health care utilization perspective. We did not capture the rationale for fluid administration so the issue of cause and effect are not easy to disentangle from these data. This was an observational study and there were differences in across the 5 categories of fluid balance, urine output and serum creatinine. However, in the adjusted models, these were taken into account. As a descriptive study, these data serve to catalogue current practice in post cardiac surgery patients and allow generation of testable hypotheses.The strengths of this study are the careful tabulation of all input and output from the time of surgery until 72 hours post operatively; that patients appeared to receive similar amounts of volume within the operative period, and had similar urine outputs. Thus, all of the differences that occurred with fluid administration took place after similar intraoperative volume resuscitation, which may permit the development of interventions to be tested in the postoperative period.UO with fluid overload or AKICr.There is accumulating literature on the benefits of restrictive fluid management strategies ,26 in crOur study has an important practical message. Attention to fluid balance, with and without perturbations in serum creatinine or oliguria, may help to more accurately identify those patients with AKI at risk of adverse outcomes. Our data suggest that oliguric patients with fluid overload may have worse outcomes than those with oliguria alone. The definition and recognition of AKI is evolving. It is important that our approach to fluid management, resuscitation and limitations in fluid accumulation similarly evolve.


The power of mobile communications has increased dramatically in recent years such that these devices (smartphone or tablet computer) can be used productively to do science If he or she is fortunate, a scientist may attend one or more scientific conferences in a year. In some fields, the number of conferences to attend is overwhelming. The time and cost expenditures required to physically participate in conferences necessitate an alternative route to access the information presented and capture it for future reference. Ideally, it would be preferable to monitor conferences remotely and at minimal or no cost. Increasingly, some scientists are using Twitter as a vehicle to summarize presentations and posters at conferences in real time, which is defined as “live tweeting.” The advantage of remote participation is that the information tweeted is open and free to anyone around the globe . From ouFor example, conferences like “Science Online”   are at o# = hashtag@ = nametag, a way to reply to someone.@ = broadcast a tweet that begins with a nametagRT = retweet, share something already tweetedHT = hat tip, acknowledge or thank a sourceDM = direct messageCX = correctionTweetup = physical meeting of tweetershttp://socialmediatoday.com/emoderation/512987/top-twitter-abbreviations-you-need-knowAdditional abbreviations can be found elsewhere: http://www.ogawadesign.com/services/twitter-for-your-biz/twitter-abbreviations-and-twitter-acronymns.htmlhttp://www.webopedia.com/quick_ref/Twitter_Dictionary_Guide.asphttp://www.abbreviations.com/acronyms/CONFAcronyms for common conferences can be found here: At the other extreme, which unfortunately is representative of most scientific conferences we have attended, there are few if any active live tweeters. This could be for several reasons: demographics of attendees, esoteric subject matter, and whether the organizer wants information to extend outside the conference halls (Gordon Conferences is one organization that may discourage tweeting on the assumption that this prevents scientists from sharing unpublished data). Sometimes the organizers of these conferences either do not actively encourage tweeting or they choose a cumbersome hashtag  that conScientists in some cases tend to be quite introverted (varying by field) so any efforts to break the ice or engage new participants at conferences are also welcome. Twitter can play an active role here to bridge or break down the gap between researcher cliques and can serve as a means to introduce you and your ideas to others in the field, without having to personally “know” them. We have found from our own experiences that Twitter interactions that initially formed online during the meeting or previous meetings can have a lasting presence in real life, forging collaborations and further expanding on discussions initiated via Twitter.In light of those observations, it's worth proposing ten simple guidelines to encourage conference organizers, conference attendees, and anyone interested who uses Twitter to enhance the spread of scientific information beyond the physical walls of the auditoria in which meetings are held. While it is possible to add many other recommendations (such as encouraging the use of Storify to combine tweets from a meeting), we believe this is a good starting point for scientists new to Twitter and perhaps previously unwilling or unable to live tweet. While we would not claim to be the absolute authorities on Twitter use at conferences, our cumulative experiences of live tweeting have enabled us to provide a short list of recommendations. These ten simple rules are certainly ripe for future refinement or replacement as other microblogging tools are developed. Of course, it's also important to remember to enjoy the conference (if you are attending in person) and please try to add some local color to the proceedings in your tweets by describing the conference locale (using pictures if permitted). Don't be afraid to add personality while providing a voice for those not physically attending.In the style of Twitter, we have kept these “rules or recommendations” to a maximum of 140 characters (so that they can in turn be tweeted).As soon as the meeting is announced, conference organizers should claim a short (6–8 characters) descriptive # that includes the year.Highlight the hashtag in all conference materials online, in print, on name badges, and on Twitter if possible.Encourage live tweeting at the conference. Session chairs can facilitate this and relay questions from the twitterosphere.Keep questions short and on the science, avoid grandstanding, encourage responsible tweeting, and avoid harassment or snarkiness.List speaker name, affiliation and conference hashtag in the first tweet; surname or initials and meeting hashtag are sufficient thereafter.Summarize presentations concisely, use hashtags for keywords, and use “@ reply” to engage individuals who can add to the discussion.Separate your own comments/viewpoints on the speaker or science being described in a presentation from the speaker's own words.Check for and raise questions from those outside the conference, returning the speaker responses to positively enforce participation.Organize tweetups so that conference attendees can meet in person and consolidate relationships and collaborations.Ensure that positive effects of tweeting at conferences, such as discoveries, publications, or collaborations, are highlighted.