[Second victim : Critical incident stress management in clinical medicine]

BACKGROUND Critical incidents in clinical medicine can have far-reaching consequences on patient health. In cases of severe medical errors they can seriously harm the patient or even lead to death. The involvement in such an event can result in a stress reaction, a so-called acute posttraumatic stress disorder in the healthcare provider, the so-called second victim of an adverse event. Psychological distress may not only have a long lasting impact on quality of life of the physician or caregiver involved but it may also affect the ability to provide safe patient care in the aftermath of adverse events. METHODS A literature review was performed to obtain information on care giver responses to medical errors and to determine possible supportive strategies to mitigate negative consequences of an adverse event on the second victim. An internet search and a search in Medline/Pubmed for scientific studies were conducted using the key words "second victim, "medical error", "critical incident stress management" (CISM) and "critical incident stress reporting system" (CIRS). Sources from academic medical societies and public institutions which offer crisis management programs where analyzed. The data were sorted by main categories and relevance for hospitals. Analysis was carried out using descriptive measures. RESULTS In disaster medicine and aviation navigation services the implementation of a CISM program is an efficient intervention to help staff to recover after a traumatic event and to return to normal functioning and behavior. Several other concepts for a clinical crisis management plan were identified. CONCLUSIONS The integration of CISM and CISM-related programs in a clinical setting may provide efficient support in an acute crisis and may help the caregiver to deal effectively with future error events and employee safety.

Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study

BACKGROUND Delayed enhancement (DE) MRI can assess the fibrotic substrate of scar-related VT. MDCT has the advantage of inframillimetric spatial resolution and better 3D reconstructions. We sought to evaluate the feasibility and usefulness of integrating merged MDCT/MRI data in 3D-mapping systems for structure-function assessment and multimodal guidance of VT mapping and ablation. METHODS Nine patients, including 3 ischemic cardiomyopathy (ICM), 3 nonischemic cardiomyopathy (NICM), 2 myocarditis, and 1 redo procedure for idiopathic VT, underwent MRI and MDCT before VT ablation. Merged MRI/MDCT data were integrated in 3D-mapping systems and registered to high-density endocardial and epicardial maps. Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were correlated to DE at MRI, and wall-thinning (WT) at MDCT. RESULTS Endocardium and epicardium were mapped with 391 ± 388 and 1098 ± 734 points per map, respectively. Registration of MDCT allowed visualization of coronary arteries during epicardial mapping/ablation. In the idiopathic patient, integration of MRI data identified previously ablated regions. In ICM patients, both DE at MRI and WT at MDCT matched areas of low voltage (overlap 94 ± 6% and 79 ± 5%, respectively). In NICM patients, wall-thinning areas matched areas of low voltage (overlap 63 ± 21%). In patients with myocarditis, subepicardial DE matched areas of epicardial low voltage (overlap 92 ± 12%). A total number of 266 LAVA sites were found in 7/9 patients. All LAVA sites were associated to structural substrate at imaging (90% inside, 100% within 18 mm). CONCLUSION The integration of merged MDCT and DEMRI data is feasible and allows combining substrate assessment with high-spatial resolution to better define structure-function relationship in scar-related VT.

Solute carriers (SLCs) in cancer

During tumor progression cells acquire an altered metabolism, either as a cause or as a consequence of an increased need of energy and nutrients. All four major classes of macromolecules are affected: carbohydrates, proteins, lipids and nucleic acids. As a result of the changed needs, solute carriers (SLCs) which are the major transporters of these molecules are differently expressed. This renders them important targets in the treatment of cancer. Blocking or activating SLCs is one possible therapeutic strategy. For example, some SLCs are upregulated in tumor cells due to the increased demand for energy and nutritional needs. Thus, blocking them and turning off the delivery of fuel or nutrients could be one way to interfere with tumor progression. Specific drug delivery to cancer cells via transporters is another approach. Some SLCs are also interesting as chemosensitizing targets because blocking or activating them may result in an altered response to chemotherapy. In this review we summarize the roles of SLCs in cancer therapy and specifically their potential as direct or indirect targets, as drug carriers or as chemosensitizing targets.

In situ dehydration behavior of veszelyite (Cu,Zn)2Zn(PO4)(OH)3·2H2O: A single-crystal X-ray study

The rare mixed copper-zinc phosphate mineral veszelyite (Cu,Zn)2Zn(PO4)(OH)3·2H2O space group P21/c, a = 7.5096(2), b = 10.2281(2), c = 9.8258(2) Å, β = 103.3040(10)°, V = 734.45(3) Å3 was investigated by in situ temperature-dependent single-crystal X-ray structure refinements. The atomic arrangement of veszelyite consists of an alternation of octahedral and tetrahedral sheets. The Jahn-Teller distorted CuO6 octahedra form sheets with eight-membered rings. The tetrahedral sheet composed of PO4 and ZnO3(OH) tetrahedra shows strong topological similarities to that of cavansite, gismondine, and kipushite.Diffraction data of a sample from Zdravo Vrelo, near Kreševo (Bosnia and Herzegovina) have been measured in steps of 25 up to 225 °C. Hydrogen positions and the hydrogen-bond system were determined experimentally from the structure refinements of data collected up to 125 °C. At 200 °C, the hydrogen-bonding scheme was inferred from bond-valence calculations and donor-acceptor distances. The hydrogen-bond system connects the tetrahedral sheet to the octahedral sheet and also braces the Cu sheet.At 150 °C, the H2O molecule at H2O2 was released and the Cu coordination (Cu1 and Cu2) decreased from originally six- to fivefold. Cu1 has a square planar coordination by four OH groups and an elongate distance to O3, whereas Cu2 has the Jahn-Teller characteristic elongate bond to H2O1. The unit-cell volume decreased 7% from originally 734.45(3) to 686.4(4) Å3 leading to a formula with 1 H2O pfu. The new phase observed above 150 °C is characterized by an increase of the c axis and a shortening of the b axis. The bending of T-O-T angles causes an increasing elliptical shape of the eight-membered rings in the tetrahedral and octahedral sheets. Moreover a rearrangement of the hydrogen-bond system was observed.At 225 °C, the structure degrades to an X-ray amorphous residual due to release of the last H2O molecule at H2O1. The stronger Jahn-Teller distortion of Cu1 relative to Cu2 suggests that Cu1 is fully occupied by Cu, whereas Cu2 bears significant Zn. H2O1 is the fifth ligand of Cu2. Zn at Cu2 is not favorable to adopt planar fourfold coordination. Thus, if the last water molecule is expelled the structure is destabilized.This study contributes to understanding the dehydration mechanism and thermal stability of supergene minerals characterized by Jahn-Teller distorted octahedra with mixed Cu, Zn occupancy.

D-dimer to Rule Out Pulmonary Embolism in Renal Insufficiency

BACKGROUND D-dimer levels are often elevated in renal insufficiency. The diagnostic accuracy of D-dimer to rule out pulmonary embolism in patients with renal insufficiency is unclear. METHODS We evaluated the data of patients presenting to our Emergency Department and receiving computed tomography angiography to rule out pulmonary embolism with measurement of D-dimer and creatinine. Glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. RESULTS There were 1305 patients included; 1067 (82%) had an estimated glomerular filtration rate (eGFR) exceeding 60 mL/min, 209 (16%) 30-60 mL/min, and 29 (2%) <30 mL/min. One hundred fifty-two patients (12%) had D-dimer below 500 μg/L. eGFR (R = -0.1122) correlated significantly with D-dimer (P <.0001). One hundred sixty-nine patients (13%) were found to have pulmonary embolism. Sensitivity of D-dimer for patients with an eGFR >60 mL/min was 96% (confidence interval [CI], 0.93-0.99) and 100% (CI, 100-100) for those with 30-60 mL/min, while specificity decreased significantly with impaired renal function. Area under the curve of the receiver operating characteristic for D-dimer was 0.734 in patients with an eGFR of >60 mL/min, and 0.673 for 30-60 mL/min. CONCLUSIONS D-dimer levels were elevated in patients with an eGFR <60 mL/min, but proved to be highly sensitive for the exclusion of pulmonary embolism. However, because almost all patients with impaired renal function had elevated D-dimer irrespective of the presence of pulmonary embolism, studies should be performed to determine renal function-adjusted D-dimer cutoffs.

Estimation of aortic pressure waveforms from 4D phase-contrast MRI

Several approaches for the non-invasive MRI-based measurement of the aortic pressure waveform over the heart cycle have been proposed in the last years. These methods are normally based on time-resolved, two-dimensional phase-contrast sequences with uni-directionally encoded velocities (2D PC-MRI). In contrast, three-dimensional acquisitions with tridirectional velocity encoding (4D PC-MRI) have been shown to be a suitable data source for detailed investigations of blood flow and spatial blood pressure maps. In order to avoid additional MR acquisitions, it would be advantageous if the aortic pressure waveform could also be computed from this particular form of MRI. Therefore, we propose an approach for the computation of the aortic pressure waveform which can be completely performed using 4D PC-MRI. After the application of a segmentation algorithm, the approach automatically computes the aortic pressure waveform without any manual steps. We show that our method agrees well with catheter measurements in an experimental phantom setup and produces physiologically realistic results in three healthy volunteers.

Vitreoretinal Interface Changes in Geographic Atrophy.

PURPOSE Geographic atrophy (GA) is the end-stage manifestation of atrophic age-related macular degeneration (AMD). The disease progresses slowly over time, eventually causing loss of central vision. Its cause and pathomechanism are not fully known. Previous studies have suggested that vitreoretinal traction (VRT) may contribute to the progression of neovascular AMD. The aim of this study was to examine whether an association between changes at the vitreoretinal interface (VRI), in particular traction (VRT), and the characteristics and progression of GA in eyes with dry AMD can be established. DESIGN Clinic-based prospective cohort study. PARTICIPANTS A total of 97 patients (age range, 61-90 years; mean, 78.4 years) with GA secondary to dry AMD were enrolled. Patients exhibiting neovascular signs on fluorescein angiography in either eye were excluded. METHODS The VRI changes were examined using spectral-domain optical coherence tomography (SD-OCT). Characteristics of GA were examined using fundus autofluorescence (FAF) imaging. All imaging was performed using a Spectralis SLO+OCT device (Heidelberg Engineering, Heidelberg, Germany); GA area was measured using the Region Finder (Heidelberg Engineering) software native to the Spectralis platform. MAIN OUTCOME MEASURES Area and increase in area of GA. RESULTS A total of 97 eyes were examined. Vitreoretinal traction was found in 39 eyes (40%). The GA area at baseline was 6.65±5.64 mm(2) in eyes with VRT and 5.73±4.72 mm(2) in eyes with no VRT. The annual rate of progression of GA area progression was 2.99±0.66 mm(2) in eyes with VRT and 1.45±0.67mm(2) in eyes without VRT. Differences between groups in both parameters were statistically significant (n = 97 total number of eyes; P<0.001). Multiple regression analysis confirmed this finding (B = 0.714, P<0.001; F3,93 = 72.542, P<0.001; adjusted R(2) = 0.691) CONCLUSIONS: Our results indicate an association between VRT and an increased rate of progression of GA area in dry AMD. Monitoring VRT may contribute to an improved estimate of the prospective time of visual loss and to a better timing of emerging therapies in dry AMD.

Genetic Engineering of Induced Pluripotent Stem Cells and Reprogramming to Motor Neurons to Elucidate Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, fatal within 1 to 5 years after onset of symptoms. About 3 out of 100’000 persons are diagnosed with ALS and there is still no cure available [1, 2]. 95% of all cases occur sporadically and the aetiology remains largely unknown [3]. However, up to now 16 genes were identified to play a role in the development of familial ALS. One of these genes is FUS that encodes for the protein fused in sarcoma (FUS). Mutations in this gene are responsible for some cases of sporadic as well as of inherited ALS [4]. FUS belongs to the family of heterogeneous nuclear ribonucleoproteins and is predicted to be involved in several cellular functions like transcription regulation, RNA splicing, mRNA transport in neurons and microRNA processing [5] Aberrant accumulation of mutated FUS has been found in the cytoplasm of motor neurons from ALS patients [6]. The mislocalization of FUS is based on a mutation in the nuclear localization signal of FUS [7]. However, it is still unclear if the cytoplasmic localization of FUS leads to a toxic gain of cytoplasmic function and/or a loss of nuclear function that might be crucial in the course of ALS. The goal of this project is to characterize the impact of ALS-associated FUS mutations on in vitro differentiated motor neurons. To this end, we edit the genome of induced pluripotent stem cells (iPSC) using transcription activator-like effector nucleases (TALENs) [8,9] to create three isogenic cell lines, each carrying an ALS-associated FUS mutation (G156E, R244C and P525L). These iPSC’s will then be differentiated to motor neurons according to a recently established protocol [10] and serve to study alterations in the transcriptome, proteome and metabolome upon the expression of ALS-associated FUS. With this approach, we hope to unravel the molecular mechanism leading to FUS-associated ALS and to provide new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of additional neurological diseases, including spinocerebellar ataxia 2 (SCA-2), spinal muscular atrophy (SMA), fragile X syndrome, and myotonic dystrophy. [1] Cleveland, D.W. et al. (2001) Nat Rev Neurosci 2(11): 806-819 [2] Sathasivam, S. (2010) Singapore Med J 51(5): 367-372 [3] Schymick, J.C. et al. (2007) Hum Mol Genet Vol 16: 233-242 [4] Pratt, A.J. et al. (2012). Degener Neurol Neuromuscul Dis 2012(2): 1-14 [5] Lagier-Tourenne, C. Hum Mol Genet, 2010. 19(R1): p. R46-64 [6] Mochizuki, Y. et al. (2012) J Neurol Sci 323(1-2): 85-92 [7] Dormann, D. et al. (2010) EMBO J 29(16): 2841-2857 [8] Hockemeyer, D. et al. (2011) Nat Biotech 29(8): 731-734 [9] Joung, J.K. and J.D. Sander (2013) Nat Rev Mol Cell Biol 14(1): 49-55 [10]Amoroso, M.W. et al. (2013) J Neurosci 33(2): 574-586.

From local perception to global perspective

Recent sociological studies show that over short time periods the large day-to-day, month-to-month or year-to-year variations in weather at a specific location can influence and potentially bias our perception of climate change, a more long-term and global phenomenon. By weighting local temperature anomalies with the number of people that experience them and considering longer time periods, we illustrate that the share of the world population exposed to warmer-than-normal temperatures has steadily increased during the past few decades. Therefore, warming is experienced by an increasing number of individuals, counter to what might be simply inferred from global mean temperature anomalies. This behaviour is well-captured by current climate models, offering an opportunity to increase confidence in future projections of climate change irrespective of the personal local perception of weather.