High resolution combined molecular and structural optical imaging of colorectal cancer in a xenograft mouse model

With the emergence of immunotherapies for cancer treatment, there is a rising clinical need to visualize the tumor microenvironment (TME) non-invasively in detail, which could be crucial to predict the efficacy of therapy. Nuclear imaging techniques enable whole-body imaging but lack the required spatial resolution. Conversely, near-infrared immunofluorescence (immuno-NIRF) is able to reveal tumor cells and/or other cell subsets in the TME by targeting the expression of a specific membrane receptor with fluorescently labeled monoclonal antibodies (mAb). Optical coherence tomography (OCT) provides three-dimensional morphological imaging of tissues without exogenous contrast agents. The combination of the two allows molecular and structural contrast at a resolution of ~15 µm, allowing for the specific location of a cell-type target with immuno-NIRF as well as revealing the three-dimensional architectural context with OCT. For the first time, combined immuno-NIRF and OCT of a tumor is demonstrated in situ in a xenograft mouse model of human colorectal cancer, targeted by a clinically-safe fluorescent mAb, revealing unprecedented details of the TME. A handheld scanner for ex vivo examination and an endoscope designed for imaging bronchioles in vivo are presented. This technique promises to complement nuclear imaging for diagnosing cancer invasiveness, precisely determining tumor margins, and studying the biodistribution of newly developed antibodies in high detail

A Consumption-Based Approach to Carbon Emission Accounting – Sectoral Differences and Environmental Benefits

In recent years there has been growing concern about the emission trade balances of countries. This is due to the fact that countries with an open economy are active players in international trade. Trade is not only a major factor in forging a country’s economic structure, but contributes to the movement of embodied emissions beyond country borders. This issue is especially relevant from the carbon accounting policy and domestic production perspective, as it is known that the production-based principle is employed in the Kyoto agreement. The research described herein was designed to reveal the interdependence of countries on international trade and the corresponding embodied emissions both on national and on sectoral level and to illustrate the significance of the consumption-based emission accounting. It is presented here to what extent a consumption-based accounting would change the present system based on production-based accounting and allocation. The relationship of CO2 emission embodied in exports and embodied in imports is analysed here. International trade can blur the responsibility for the ecological effects of production and consumption and it can lengthen the link between consumption and its consequences. Input-output models are used in the methodology as they provide an appropriate framework for climate change accounting. The analysis comprises an international comparative study of four European countries (Germany, the United Kingdom, the Netherlands, and Hungary) with extended trading activities and carbon emissions. Moving from a production-based approach in climate policy to a consumption-based principle and allocation approach would help to increase the efficiency of emission reductions and would force countries to rethink their trading activities in order to decrease the environmental load of production activities. The results of this study show that it is important to distinguish between the two emission accounting approaches, both on the global and the local level

Earlier Application of Percutaneous Cardiopulmonary Support Rescues Patients from Severe Cardiopulmonary Failure Using the APACHE III Scoring System

Percutaneous cardiopulmonary support (PCPS) is a widely accepted treatment for severe cardiopulmonary failure. This system, which uses a percutaneous approach and autopriming devices, can be rapidly applied in emergency situations. We sought to identify the risk factors that could help predict in-hospital mortality, and to assess its outcomes in survivors. During a 2-yr period, 50 patients underwent PCPS for the treatment of severe cardiopulmonary failure, and of those, 22 (44%) were classified as survivors and 28 (56%) as non-survivors. We compared the 2 groups for risk factors of in-hospital mortality and to establish proper PCPS timing. Twenty patients underwent PCPS for acute myocardial infarction, 20 for severe cardiopulmonary failure after cardiac surgery, 7 for acute respiratory distress syndrome, and 3 for acute myocarditis. Multivariate analysis showed that an acute physiology, age, and chronic health evaluation (APACHE) III score ≥50 prior to PCPS was the only significant predictor of in-hospital mortality (P=0.001). Overall 18-month survival was 42.2%. Cox analysis showed patients with APACHE III scores ≥50 had a poor prognosis (P=0.001). Earlier application of PCPS, and other preemptive strategies designed to optimize high-risk patients, may improve patient outcomes. Identifying patients with high APACHE scores at the beginning of PCPS may predict in-hospital mortality. Survivors, particularly those with higher APACHE scores, may require more frequent follow-up to improve overall survival

Limited effect of patient and disease characteristics on compliance with hospital antimicrobial guidelines

Objective: Physicians frequently deviate from guidelines that promote prudent use of antimicrobials. We explored to what extent patient and disease characteristics were associated with compliance with guideline recommendations for three common infections. Methods: In a 1-year prospective observational study, 1,125 antimicrobial prescriptions were analysed for compliance with university hospital guidelines. Results: Compliance varied significantly between and within the groups of infections studied. Compliance was much higher for lower respiratory tract infections (LRTIs; 79%) than for sepsis (53%) and urinary tract infections (UTIs; 40%). Only predisposing illnesses and active malignancies were associated with more compliant prescribing, whereas alcohol/ intravenous drug abuse and serum creatinine levels > 130 mu mol/l were associated with less compliant prescribing. Availability of culture results had no impact on compliance with guidelines for sepsis but was associated with more compliance in UTIs and less in LRTIs. Narrowing initial broad-spectrum antimicrobial therapy to cultured pathogens was seldom practised. Most noncompliant prescribing concerned a too broad spectrum of activity when compared with guideline-recommended therapy. Conclusion: Patient characteristics had only a limited impact on compliant prescribing for a variety of reasons. Physicians seemed to practise defensive prescribing behaviour, favouring treatment success in current patients over loss of effectiveness due to resistance in future patients

Would you be surprised if this patient died?: Preliminary exploration of first and second year residents' approach to care decisions in critically ill patients

BACKGROUND: How physicians approach decision-making when caring for critically ill patients is poorly understood. This study aims to explore how residents think about prognosis and approach care decisions when caring for seriously ill, hospitalized patients. METHODS: Qualitative study where we conducted structured discussions with first and second year internal medicine residents (n = 8) caring for critically ill patients during Medical Intensive Care Unit Ethics and Discharge Planning Rounds. Residents were asked to respond to questions beginning with "Would you be surprised if this patient died?" RESULTS: An equal number of residents responded that they would (n = 4) or would not (n = 4) be surprised if their patient died. Reasons for being surprised included the rapid onset of an acute illness, reversible disease, improving clinical course and the patient's prior survival under similar circumstances. Residents reported no surprise with worsening clinical course. Based on the realization that their patient might die, residents cited potential changes in management that included clarifying treatment goals, improving communication with families, spending more time with patients and ordering fewer laboratory tests. Perceived or implied barriers to changes in management included limited time, competing clinical priorities, "not knowing" a patient, limited knowledge and experience, presence of diagnostic or prognostic uncertainty and unclear treatment goals. CONCLUSIONS: These junior-level residents appear to rely on clinical course, among other factors, when assessing prognosis and the possibility for death in severely ill patients. Further investigation is needed to understand how these factors impact decision-making and whether perceived barriers to changes in patient management influence approaches to care

Modelling thirty-day mortality in the acute respiratory distress syndrome (ARDS) in an adult ICU

Publisher's copy made available with the permission of the publisher © Australian Society of AnaesthetistsVariables predicting thirty-day outcome from Acute Respiratory Distress Syndrome (ARDS) were analysed using Cox regression structured for time-varying covariates. Over a three-year period, 1996-1998, consecutive patients with ARDS (bilateral chest X-ray opacities, PaO₂/FiO₂ ratio of <200 and an acute precipitating event) were identified using a prospective computerized data base in a university teaching hospital ICU. The cohort, 106 mechanically ventilated patients, was of mean (SD) age 63.5 (15.5) years and 37% were female. Primary lung injury occurred in 45% and 24% were postoperative. ICU-admission day APACHE II score was 25 (8); ARDS onset time from ICU admission was 1 day (median: range 0-16) and 30 day mortality was 41% (95% CI: 33%-51%). At ARDS onset, PaO₂/FiO₂ ratio was 92 (31), 81% had four-quadrant chest X-ray opacification and lung injury score was 2.75 (0.45). Average mechanical ventilator tidal volume was 10.3 ml/ predicted kg weight. Cox model mortality predictors (hazard ratio, 95% CI) were: APACHE II score, 1.15 (1.09-1.21); ARDS lag time (days), 0.72 (0.58-0.89); direct versus indirect injury, 2.89 (1.45-5.76); PaO₂/FiO₂ ratio, 0.98 (0.97-0.99); operative versus non-operative category, 0.24 (0.09-0.63). Time-varying effects were evident for PaO₂/FiO₂ ratio, operative versus non-operative category and ventilator tidal volume assessed as a categorical predictor with a cut-point of 8 ml/kg predicted weight (mean tidal volumes, 7.1 (1.9) vs 10.7 (1.6) ml/kg predicted weight). Thirty-day survival was improved for patients ventilated with lower tidal volumes. Survival predictors in ARDS were multifactorial and related to patient-injury-time interaction and level of mechanical ventilator tidal volume.J. L. Moran, P. J. Solomon, V. Fox, M. Salagaras, P. J. Williams, K. Quinlan, A. D. Berstenhttp://www.aaic.net.au/Article.asp?D=200332

Effect of acute kidney injury on mortality and hospital stay in patient with severe acute pancreatitis

AimSevere acute pancreatitis (SAP) is believed to be a major risk factor leading to acute kidney injury (AKI) among critically ill patients, but little is known about SAP‐induced AKI. We study the incidence of AKI defined by the Acute Kidney Injury Network (AKIN) criteria and the risk factors associated with outcomes among SAP‐induced AKI patients.MethodWe conducted a multicenter retrospective study of critically ill SAP‐induced AKI patients during the period August 2009 to June 2013. Data on enrolled patients were retrieved from electronic records. Univariate and multiple regression analyses were performed.ResultsAmong a total of 414 SAP patients admitted to intensive care units(ICU), 287 (69.3%) developed AKI during their ICU stay, with 16.7%, 18.4%, and 34.3% classified as AKI stage I,II, and III, respectively. SAP‐induced AKI patients experienced a significantly higher ICU mortality than those without AKI. The risk factors associated with ICU mortality among SAP‐induced AKI patients included ACS (odds ratio (OR) 10.58), RRT (OR 3.31), sepsis (OR 2.46), CTSI (OR 3.01), APACHE II score (OR 1.82), AKI III (OR 1.38), ICU‐length‐of‐stay (OR 1.04), and multi‐organ failure.ConclusionsThe paper represents the first attempt to investigate the etiology and epidemiology of AKI following SAP under the AKIN criteria among critically ill patients. Several independent risk factors were found to be associated with ICU mortality for AKI patients. The findings may pinpoint crucial therapeutic measures for preventing AKI among a vulnerable population and for more effective management of SAP‐induced AKI to improve the quality of intensive care.Summary at a GlanceIn this retrospective study of AKI following acute pancreatitis, the authors identify risk factors associated with mortality. These findings provide a basis for focussing on high risk patients for future trials of therapeutic interventions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111910/1/nep12439.pd

Impact of increased mean arterial pressure on skin microcirculatory oxygenation in vasopressor-requiring septic patients : an interventional study

Background: Heterogeneity of microvascular blood flow leading to tissue hypoxia is a common finding in patients with septic shock. It may be related to suboptimal systemic perfusion pressure and lead to organ failure. Mapping of skin microcirculatory oxygen saturation and relative hemoglobin concentration using hyperspectral imaging allows to identify heterogeneity of perfusion and perform targeted measurement of oxygenation. We hypothesized that increasing mean arterial pressure would result in improved oxygenation in areas of the skin with most microvascular blood pooling. Methods: We included adult patients admitted to the intensive care unit within the previous 24 h with sepsis and receiving a noradrenaline infusion. Skin oxygen saturation was measured using hyperspectral imaging-based method at baseline and after the increase in mean arterial pressure by 20 mm Hg by titration of noradrenaline doses. The primary outcome was an increase in skin oxygen saturation depending upon disease severity. Results: We studied 30 patients with septic shock. Median skin oxygen saturation changed from 26.0 (24.5–27.0) % at baseline to 30.0 (29.0–31.0) % after increase in mean arterial pressure (p=0.04). After adjustment for baseline saturation, patients with higher SOFA scores achieved higher oxygen saturation after the intervention (r2=0.21; p=0.02). Skin oxygen saturation measured at higher pressure was found to be marginally predictive of mortality (OR: 1.10; 95% CI 1.00–1.23; p=0.053). Conclusions: Improvement of microcirculatory oxygenation can be achieved with an increase in mean arterial pressure in most patients. Response to study intervention is proportional to disease severity.publishersversionPeer reviewe

A CRISPR-Cas9-engineered mouse model for GPI anchor deficiency mirrors human phenotype and shows hippocampal synaptic dysfunctions

Pathogenic germline mutations in PIGV lead to glycosylphosphatidylinositol biosynthesis deficiency. Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol anchor pathway show cognitive impairments, a motor delay and in many cases epilepsy. Thus far, the pathophysiology underlying the disease remains unclear and suitable rodent models that mirror human pathophysiology have not been available. We therefore generated a mouse model using CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, at a site that is also conserved in mice, Pigv:c.1022C>A (p.A341E). Reflecting the human pathology mutant Pigv(341E) mice showed deficits in motor coordination and cognitive impairment with poorer long-term spatial memory than wild-type mice, as well as alterations in sociability and sleep patterns. Furthermore, immunohistochemistry showed decreased synaptophysin-immunoreactivity and electrophysiology recordings demonstrated reduced hippocampal synaptic transmission in Pigv(341E) mice that may underlie impaired memory formation. To gain a deeper and broader molecular understanding of the consequences of glycosylphosphatidylinositol anchor deficiency, we performed single-cell RNA sequencing on acutely isolated hippocampal cells of Pigv(341E) and wild-type mice. We found that hippocampal cells from adult Pigv(341E) mice exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction of Abl1 transcripts in several cell clusters suggests a link to the signaling pathway of glycosylphosphatidylinositol-anchored ephrins. We also observed increased levels of Hdc that might affect histamine metabolism with consequences in circadian rhythm. In summary, we present here the first mouse model with a patient-specific hypomorphic mutation that mirrors the human phenotype and shows a hippocampal synaptic defect. This new mouse model will not only open the doors for further investigation into the pathophysiology of glycosylphosphatidylinositol biosynthesis deficiency in future studies, but will also deepen our understanding in the role of glycosylphosphatidylinositol-anchor related pathways in brain development

Serum levels of S100B from jugular bulb as a biomarker of poor prognosis in patients with severe acute brain injury

Aims/background To evaluate the correlation between protein S100B concentrations measured in the jugular bulb as well as at peripheral level and the prognostic usefulness of this marker. Methods A prospective study of all patients admitted to the intensive care unit with acute brain damage was carried out. Peripheral and jugular bulb blood samples were collected upon admission and every 24 h for three days. The endpoints were brain death diagnosis and the Glasgow Outcome Scale score after 6 months. Results A total of 83 patients were included. Jugular protein S100B levels were greater than systemic levels upon admission and also after 24 and 72 h (mean difference > 0). Jugular protein S100B levels showed acceptable precision in predicting brain death both upon admission [AUC 0.67 (95% CI 0.53?0.80)] and after 48 h [AUC 0.73 (95% CI 0.57?0.89)]. Similar results were obtained regarding the capacity of jugular protein S100B levels upon admission to predict an unfavourable outcome (AUC 0.69 (95% CI 0.56?0.79)). The gradient upon admission (jugular-peripheral levels) showed its capacity to predict the development of brain death [AUC 0.74 (95% CI 0.62?0.86)] and together with the Glasgow Coma Scale constituted the independent factors associated with the development of brain death. Conclusion Regional protein S100B determinations are higher than systemic determinations, thus confirming the cerebral origin of protein S100B. The transcranial protein S100B gradient is correlated to the development of brain death.This study has been supported by grants from the Marqués de Valdecilla Foundation - IFIMAV (API 10/02) and the Spanish Ministry of Science - Carlos III Health Institute (PI080058). The protein S100B electrochemoluminescence assay kits were a generous donation from Roche Diagnostics, Mannheim, Germany The authors report no conflicts of interest. The authors alone are responsible for the contents and writing of the paper